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139 results on '"Hématopoïèse normale et pathologique (U1170 Inserm)"'

1. Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α-granules

Author: Paquita Nurden, Philippe Rameau, Xavier Pillois, Vasiliki Gkalea, Najet Debili, Marie-Christine Alessi, Marie Favier, Hana Raslova, Jean-Claude Bordet, Alan T. Nurden, Rémi Favier, Nutrition, obésité et risque thrombotique ( NORT ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hémostase, Inflammation et sepsis, Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-VetAgro Sup ( VAS ), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Haut-Lévêque, CHU Bordeaux [Bordeaux]-Université Sciences et Technologies - Bordeaux 1, Plateforme imagerie et cytométrie ( PFIC ), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse ( AMMICa ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), IHU-LIRYC, CHU Bordeaux [Bordeaux]-Université Bordeaux Segalen - Bordeaux 2, Gironde, Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hémostase, Inflammation et sepsis (EA 4609), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux], Plateforme imagerie et cytométrie (PFIC), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Goletto, Marie-Hélène, Université Sciences et Technologies - Bordeaux 1 (UB)-CHU Bordeaux [Bordeaux], Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre recherche en CardioVasculaire et Nutrition (C2VN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Fibrinolyse et Pathologie Vasculaire, and Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Blood Platelets, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0301 basic medicine, Platelet Aggregation, Integrin, Integrin alpha2, integrin a2IIbb3, Platelet Glycoprotein GPIIb-IIIa Complex, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Cytoplasmic Granules, medicine.disease_cause, inherited macrothrombocytopenia, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Computer Simulation, Family, Platelet, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Gene, enlarged α-granules, ComputingMilieux_MISCELLANEOUS, Genetics, Mutation, Integrin beta3, [ SDV.IDA ] Life Sciences [q-bio]/Food engineering, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Thrombocytopenia, Molecular biology, Phenotype, platelet function defects, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Article RECHERCHE, biology.protein, Salt bridge, Megakaryocytes, 030215 immunology
Abstract: International audience; Rare gain‐of‐function mutations within the ITGA2B or ITGB3 genes have been recognized to cause macrothrombocytopenia (MTP). Here we report three new families with autosomal dominant (AD) MTP, two harboring the same mutation of ITGA2B, αIIbR995W, and a third family with an ITGB3 mutation, β3D723H. In silico analysis shows how the two mutated amino acids directly modify the salt bridge linking the intra‐cytoplasmic part of αIIb to β3 of the integrin αIIbβ3. For all affected patients, the bleeding syndrome and MTP was mild to moderate. Platelet aggregation tended to be reduced but not absent. Electron microscopy associated with a morphometric analysis revealed large round platelets; a feature being the presence of abnormal large α‐granules with some giant forms showing signs of fusion. Analysis of the maturation and development of megakaryocytes reveal no defect in their early maturation but abnormal proplatelet formation was observed with increased size of the tips. Interestingly, this study revealed that in addition to the classical phenotype of patients with αIIbβ3 intracytoplasmic mutations there is an abnormal maturation of α‐granules. It is now necessary to determine if this feature is a characteristic of all mutations disturbing the αIIb R995/β3 D723 salt bridge.
Published: 2017
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2. A constitutive BCL2 down-regulation aggravates the phenotype of PKD1-mutant-induced polycystic kidney disease

Author: Virginie Carmignac, David Vandroux, Nathalie Droin, Patrick Callier, Guillaume Meurice, Laurence Faivre, Noémie Pata-Merci, Romaric Loffroy, Christel Thauvin-Robinet, Ange-Line Bruel, Romain Da Costa, Julien Thevenon, Olivier Bouchot, Laurence Duplomb, Eric Solary, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie cardio-vasculaire et thoracique (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), FHU TRANSLAD (CHU de Dijon), Laboratoire de cytogénétique (CHU de Dijon), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon), Plateforme de Génomique [Gustave Roussy], Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), NVH Medicinal Biotechnology (Dijon), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), FHU TRANSLAD, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse ( AMMICa ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Plateforme de Génomique, Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Université Paris-Sud 11 - Faculté de médecine ( UP11 UFR Médecine )
Subjects: Adult, Male, 0301 basic medicine, TRPP Cation Channels, phenotype, bcl2 gene, Biology, micro rna, Mice, 03 medical and health sciences, down-regulation, symptom aggravating factors, hemic and lymphatic diseases, t-lymphocyte, Gene expression, Genetics, medicine, Polycystic kidney disease, Animals, Humans, Genetic Predisposition to Disease, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, genes, Molecular Biology, Gene, Genetics (clinical), Exome sequencing, Mice, Knockout, PKD1, apoptosis, Exons, General Medicine, Polycystic Kidney, Autosomal Dominant, medicine.disease, Phenotype, Pedigree, Up-Regulation, 3. Good health, MicroRNAs, 030104 developmental biology, MRNA Sequencing, Proto-Oncogene Proteins c-bcl-2, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Immunology, Cancer research, Lymphocytopenia, polycystic kidney diseases, bcl-2 protein
Abstract: IF 5.340; International audience; The main identified function of BCL2 protein is to prevent cell death by apoptosis. Mice knock-out for Bcl2 demonstrate growth retardation, severe polycystic kidney disease (PKD), gray hair and lymphopenia, and die prematurely after birth. Here, we report a 40-year-old male referred to for abdominal and thoracic aortic dissection with associated aortic root aneurysm, PKD, lymphocytopenia with a history of T cell lymphoblastic lymphoma, white hair since the age of 20, and learning difficulties. PKD, which was also detected in the father and sister, was related to an inherited PKD1 mutation. The combination of PKD with gray hair and lymphocytopenia was also reminiscent of Bcl2-/- mouse phenotype. BCL2 gene transcript and protein level were observed to be dramatically decreased in patient peripheral blood T-cells and in his aorta vascular wall cells, which was not detected in parents and sister T-cells, suggesting an autosomal recessive inheritance. Accordingly, spontaneous apoptosis of patient T-cells was increased and could be rescued through stimulation with an anti-CD3 antibody. Direct sequencing of BCL2 gene exons, promoter and 3'UTR region as well as BCL2 mRNA sequencing failed in identifying any pathogenic variant. Array-CGH was also normal and whole exome sequencing of the patient, parents and sister DNA did not detect any significant variant in genes encoding Bcl2-interacting proteins. miRNA array identified an up-regulation of miR-181a, which is a known regulator of BCL2 expression. Altogether, miR-181a-mediated decrease in BCL2 gene expression could be a modifying factor that aggravates the phenotype of a PKD1 constitutive variant.
Published: 2017
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3. Gap junction-mediated transfer of miR-145-5p from microvascular endothelial cells to colon cancer cells inhibits angiogenesis

Author: Gaëtan Jego, Arlette Hammann, Eric Solary, Carmen Garrido, Kevin Berthenet, Dominique Thuringer, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Centre National de la Recherche Scientifique (CNRS), Institut National de la Sante et de la Recherche Medicale (INSERM), Ligue Nationale Contre le Cancer, Agence Nationale de la Recherche, Institut National du Cancer (INCa), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), and UNICANCER
Subjects: 0301 basic medicine, Cell signaling, Angiogenesis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Communication, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Cell Line, Tumor, microRNA, Bystander effect, Humans, Medicine, Neovascularization, Pathologic, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, business.industry, micro-RNA, Gap junction, Endothelial Cells, Gap Junctions, tubulogenesis, Coculture Techniques, Microvesicles, Cx43, Cell biology, Endothelial stem cell, MicroRNAs, 030104 developmental biology, Oncology, GJIC, Colonic Neoplasms, Cancer cell, Immunology, business, Research Paper, colorectal tumor
Abstract: IF 5.008; International audience; Gap junctional communication between cancer cells and blood capillary cells is crucial to tumor growth and invasion. Gap junctions may transfer microRNAs (miRs) among cells. Here, we explore the impact of such a transfer in co-culture assays, using the antitumor miR-145 as an example. The SW480 colon carcinoma cells form functional gap junction composed of connexin-43 (Cx43) with human microvascular endothelial cells (HMEC). When HMEC are loaded with miR-145-5p mimics, the miR-145 level drastically increases in SW480. The functional inhibition of gap junctions, using either a gap channel blocker or siRNA targeting Cx43, prevents this increase. The transfer of miR-145 also occurs from SW480 to HMEC but not in non-contact co-cultures, excluding the involvement of soluble exosomes. The miR-145 transfer to SW480 up-regulates their Cx43 expression and inhibits their ability to promote angiogenesis. Our results indicate that the gap junctional communication can inhibit tumor growth by transferring miRs from one endothelial cell to neighboring tumor cells. This "bystander" effect could find application in cancer therapy.
Published: 2016
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4. Regulation of the positive transcriptional effect of PLZF through a non-canonical EZH2 activity

Author: Christel Guillouf, Estelle Duprez, Abdessamad El-Kaoutari, Jean-Christophe Andrau, Lia N’guyen, Sylvain Garciaz, Guillaume Tiberi, Myriam Koubi, Muhammad Ahmad Maqbool, Mathilde Poplineau, Julien Vernerey, Andrew J. Saurin, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille ( CRCM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes-Aix Marseille Université ( AMU ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Biologie du Développement de Marseille ( IBDM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Transcription, Genetic, [SDV.CAN]Life Sciences [q-bio]/Cancer, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, macromolecular substances, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Histones, 03 medical and health sciences, Histone H3, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Humans, Enhancer of Zeste Homolog 2 Protein, Promyelocytic Leukemia Zinc Finger Protein, Cell Self Renewal, Transcription factor, Regulation of gene expression, Binding Sites, Gene regulation, Chromatin and Epigenetics, EZH2, Polycomb Repressive Complex 2, Cell Differentiation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Hematopoietic Stem Cells, Chromatin, Neoplasm Proteins, Cell biology, 030104 developmental biology, Gene Expression Regulation, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Histone methyltransferase, Histone Methyltransferases, biology.protein, H3K4me3, PRC2, Protein Binding, Transcription Factors
Abstract: International audience; The transcription factor PLZF (promyelocytic leukemia zinc finger protein) acts as an epigenetic regulator balancing self-renewal and differentiation of hematopoietic cells through binding to various chromatin-modifying factors. First described as a transcriptional repressor, PLZF is also associated with active transcription, although the molecular bases underlying the differences are unknown. Here, we reveal that in a hematopoietic cell line, PLZF is predominantly associated with transcribed genes. Additionally, we identify a new association between PLZF and the histone methyltransferase, EZH2 at the genomic level. We find that co-occupancy of PLZF and EZH2 on chromatin at PLZF target genes is not associated with SUZ12 or trimethylated lysine 27 of histone H3 (H3K27me3) but with the active histone mark H3K4me3 and active transcription. Removal of EZH2 leads to an increase of PLZF binding and increased gene expression. Our results suggest a new role of EZH2 in restricting PLZF positive transcriptional activity independently of its canonical PRC2 activity.
Published: 2018
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5. Rituximab after Autologous Stem-Cell Transplantation in Mantle-Cell Lymphoma

Author: Steven, Le Gouill, Catherine, Thieblemont, Lucie, Oberic, Anne, Moreau, Krimo, Bouabdallah, Caroline, Dartigeas, Gandhi, Damaj, Thomas, Gastinne, Vincent, Ribrag, Pierre, Feugier, Olivier, Casasnovas, Hacène, Zerazhi, Corinne, Haioun, Hervé, Maisonneuve, Roch, Houot, Fabrice, Jardin, Eric, Van Den Neste, Olivier, Tournilhac, Katell, Le Dû, Franck, Morschhauser, Guillaume, Cartron, Luc-Matthieu, Fornecker, Danielle, Canioni, Mary, Callanan, Marie C, Béné, Gilles, Salles, Hervé, Tilly, Thierry, Lamy, Remy, Gressin, Olivier, Hermine, Marie-Helène, Delfau-Larue, Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Mathématiques de Jussieu (IMJ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Hématologie [CHU Amiens], CHU Amiens-Picardie, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Institut Gustave Roussy (IGR), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Médecine Interne Onco-hématologie, Centre Hospitalier Général, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'hématologie, Centre hospitalier La Roche-Sur-Yon, CHU Pontchaillou [Rennes], Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cliniques Universitaires Saint-Luc [Bruxelles], Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Clinique Victor Hugo [Le Mans], Biophysique, Médecine Nucléaire et Technologies Médicales (EA 1049), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), CHU Strasbourg, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), INSERM U823, équipe 7 (Voies Oncogéniques Des Hémopathies Malignes), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre hospitalier universitaire de Nantes ( CHU Nantes ), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Institut Universitaire du Cancer de Toulouse - Oncopole ( IUCT Oncopole - UMR 1037 ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Nutrition, croissance et cancer (U 1069) ( N2C ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Tours, CHU Caen, Université Paris-Sud - Paris 11 ( UP11 ), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy ( IGR ), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), University Hospital of Nancy, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service de Médecine Onco-hématologie [La Roche sur Yon], Centre Hospitalier Universitaire de Nantes, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou, Microenvironment, Cell Differentiation, Immunology and Cancer ( MICMAC ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Groupe d'étude des proliférations lymphoïdes ( GPL ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias - Clermont Auvergne ( CHELTER ), Université Clermont Auvergne ( UCA ), Hôpital Claude Huriez-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Génétique, Immunothérapie, Chimie et Cancer ( GICC ), Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Institut Pluridisciplinaire Hubert Curien ( IPHC ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Adaptateurs de signalisation en hématologie ( ASIH ), Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Hôpital Pontchaillou, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours, and Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)
Subjects: Adult, Male, medicine.medical_specialty, Randomization, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Lymphoma, Mantle-Cell, Hematopoietic stem cell transplantation, Transplantation, Autologous, Dexamethasone, Maintenance Chemotherapy, 03 medical and health sciences, 0302 clinical medicine, Autologous stem-cell transplantation, Maintenance therapy, Antineoplastic Combined Chemotherapy Protocols, Humans, Immunologic Factors, Medicine, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, ComputingMilieux_MISCELLANEOUS, Aged, Proportional Hazards Models, business.industry, Cytarabine, Hematopoietic Stem Cell Transplantation, General Medicine, Middle Aged, medicine.disease, Combined Modality Therapy, Survival Analysis, 3. Good health, Lymphoma, Surgery, Transplantation, 030220 oncology & carcinogenesis, Female, Mantle cell lymphoma, Rituximab, Cisplatin, business, 030215 immunology, medicine.drug
Abstract: Mantle-cell lymphoma is generally incurable. Despite high rates of complete response after initial immunochemotherapy followed by autologous stem-cell transplantation, patients have relapses. We investigated whether rituximab maintenance therapy at a dose of 375 mg per square meter of body-surface area administered every 2 months for 3 years after transplantation would prolong the duration of response.In a phase 3 trial involving 299 patients who were younger than 66 years of age at diagnosis, we randomly assigned 240 patients to receive rituximab maintenance therapy or to undergo observation after autologous stem-cell transplantation (120 patients per group); 59 patients did not undergo randomization. The primary end point was event-free survival (with an event defined as disease progression, relapse, death, allergy to rituximab, or severe infection) after transplantation among patients who underwent randomization.After four courses of immunochemotherapy induction (rituximab, dexamethasone, cytarabine, and a platinum derivative [R-DHAP]), the overall response rate was 89%, and the complete response rate 77%. Transplantation was performed in 257 patients. The median follow-up from randomization after transplantation was 50.2 months (range, 46.4 to 54.2). Starting from randomization, the rate of event-free survival at 4 years was 79% (95% confidence interval [CI], 70 to 86) in the rituximab group versus 61% (95% CI, 51 to 70) in the observation group (P=0.001). The rate of progression-free survival at 4 years was 83% (95% CI, 73 to 88) in the rituximab group versus 64% (95% CI, 55 to 73) in the observation group (P0.001). The rate of overall survival was 89% (95% CI, 81 to 94) in the rituximab group versus 80% (95% CI, 72 to 88) in the observation group (P=0.04). According to a Cox regression unadjusted analysis, the rate of overall survival at 4 years was higher in the rituximab group than in the observation group (hazard ratio for death, 0.50; 95% CI, 0.26 to 0.99; P=0.04).Rituximab maintenance therapy after transplantation prolonged event-free survival, progression-free survival, and overall survival among patients with mantle-cell lymphoma who were younger than 66 years of age at diagnosis. (Funded by Roche and Amgen; LyMa ClinicalTrials.gov number, NCT00921414 .).
Published: 2017
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6. High sensitivity of the Hematoflow™ solution for chronic myelomonocytic leukemia screening

Author: Vazquez, Romain, Roussel, Mikaël, Badaoui, Bouchra, Freynet, Nicolas, Tarfi, Sihem, Solary, Eric, Selimoglu-Buet, Dorothée, Wagner-Ballon, Orianne, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Pontchaillou [Rennes], Jonchère, Laurent, Assistance publique - Hôpitaux de Paris (AP-HP), Microenvironment, Cell Differentiation, Immunology and Cancer ( MICMAC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Biomécanique cellulaire et respiratoire ( BCR ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Département d'Hématologie et d'Immunologie Biologiques, CHU Henri Mondor, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.IB] Life Sciences [q-bio]/Bioengineering, chronic myelomonocytic leukemia, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Leukemia, Myelomonocytic, Chronic, classical monocyte accumulation, Flow Cytometry, Sensitivity and Specificity, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Solutions, [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, Humans, reactive monocytosis, [SDV.IB]Life Sciences [q-bio]/Bioengineering, HematoflowTM
Abstract: International audience; Background: Accumulation of classical monocytes CD14++CD16– (also called MO1) ≥ 94% can accurately distinguish chronic myelomonocytic leukemia (CMML) from reactive monocytosis. The HematoFlow™ solution, able to quantify CD16 negative monocytes, could be a useful tool to manage monocytosis which remains a common issue in routine laboratories.Methods: Classical monocytes were quantified from 153 whole blood samples collected on EDTA using both flow cytometry methods, either MO1 percentage determination by the multiparameter assay previously published and regarded here as the reference method, or CD16 negative monocyte percentage determination by the means of HematoFlow™.Results: Both methods of classical monocyte percentage determination were highly and significantly correlated (r = 0.87, P
Published: 2017
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7. DNA damage and S phase-dependent E2F1 stabilization requires the cIAP1 E3-ubiquitin ligase and is associated with K63-poly-ubiquitination on lysine 161/164 residues

Author: Glorian, Valérie, Allègre, Jennifer, Berthelet, Jean, Dumetier, Baptiste, Boutanquoi, Pierre-Marie, Droin, Nathalie, Kayaci, Cémile, Cartier, Jessy, Gemble, Simon, Marcion, Guillaume, Gonzalez, Daniel, Boidot, Romain, Garrido, Carmen, Michaud, Olivier, Solary, Eric, Dubrez, Laurence, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: endocrine system, Transcription, Genetic, polysialic acid, HDL, Ubiquitin-Protein Ligases, Arginine, Methylation, Inhibitor of Apoptosis Proteins, S Phase, LDL, Mice, Structure-Activity Relationship, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Animals, Humans, hypothalamus, Polyubiquitin, synaptic plasticity, Protein Stability, Lysine, Ubiquitination, Correction, Original Article, biological phenomena, cell phenomena, and immunity, atherosclerosis, E2F1 Transcription Factor, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, DNA Damage
Abstract: IF 5.965; International audience; The E2F transcription factor 1 is subtly regulated along the cell cycle progression and in response to DNA damage by post-translational modifications. Here, we demonstrated that the E3-ubiquitin ligase cellular inhibitor of apoptosis 1 (cIAP1) increases E2F1 K63-poly-ubiquitination on the lysine residue 161/164 cluster, which is associated with the transcriptional factor stability and activity. Mutation of these lysine residues completely abrogates the binding of E2F1 to CCNE, TP73 and APAF1 promoters, thus inhibiting transcriptional activation of these genes and E2F1-mediated cell proliferation control. Importantly, E2F1 stabilization in response to etoposide-induced DNA damage or during the S phase of cell cycle, as revealed by cyclin A silencing, is associated with K63-poly-ubiquitinylation of E2F1 on lysine 161/164 residues and involves cIAP1. Our results reveal an additional level of regulation of the stability and the activity of E2F1 by a non-degradative K63-poly-ubiquitination and uncover a novel function for the E3-ubiquitin ligase cIAP1.
Published: 2017
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8. The severe phenotype of Diamond-Blackfan anemia is modulated by heat shock protein 70

Author: Narla Mohandas, Hélène Moniz, Michael Dussiot, Carmen Garrido, Sarah Rio, Narjesse Karboul, Olivier Hermine, Marc Gastou, Jérôme Larghero, Lydie Da Costa, Margaux Sevin, Thierry Leblanc, Eric Solary, Patrick Gonin, William Vainchenker, Anupama Narla, Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge ( Labex Gr-Ex ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de recherche sur l'inflamation - UMR 1149, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme d’évaluation préclinique ( PFEP ), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse ( AMMICa ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Saint-Louis, Unité de Thérapie Cellulaire, Institut Universitaire d’Hématologie, Stanford University School of Medicine [Stanford], Stanford University [Stanford], Red Cell Physiology Laboratory [New York, USA], New York Blood Center - NYBC, Centre de recherche sur l'Inflammation ( CRI ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Plateforme d’évaluation préclinique (PFEP), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, New York Blood Center, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Identification, Apoptosis-Inducing Factor, Gata1 Mutations, Inhibits Apoptosis, Biology, Hsp70, 03 medical and health sciences, Germline mutation, Red Cells, Iron, and Erythropoiesis, hemic and lymphatic diseases, medicine, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Nuclear Import, Erythropoiesis, Diamond–Blackfan anemia, Human Erythroblasts, Bone marrow failure, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, GATA1, Hematology, medicine.disease, Phenotype, Molecular biology, 3. Good health, 030104 developmental biology, Ribosomal-Proteins, Protein Gene Deletions, Haploinsufficiency
Abstract: International audience; Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome that exhibits an erythroid-specific phenotype. In at least 70% of cases, DBA is related to a haploinsufficient germ line mutation in a ribosomal protein (RP) gene. Additional cases have been associated with mutations in GATA1. We have previously established that the RPL11+/Mut phenotype is more severe than RPS19+/Mut phenotype because of delayed erythroid differentiation and increased apoptosis of RPL11+/Mut erythroid progenitors. The HSP70 protein is known to protect GATA1, the major erythroid transcription factor, from caspase-3 mediated cleavage during normal erythroid differentiation. Here, we show that HSP70 protein expression is dramatically decreased in RPL11+/Mut erythroid cells while being preserved in RPS19+/Mut cells. The decreased expression of HSP70 in RPL11+/Mut cells is related to an enhanced proteasomal degradation of polyubiquitinylated HSP70. Restoration of HSP70 expression level in RPL11+/Mut cells reduces p53 activation and rescues the erythroid defect in DBA. These results suggest that HSP70 plays a key role in determining the severity of the erythroid phenotype in RP-mutation–dependent DBA.
Published: 2017
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9. Sequencing of the hypoxia pathway genes in patients with congenital erythrocytoses by next generation sequencing

Author: Girodon, F., Pacault, F., Airaud, M., Garrec, C., Corbineau, S., Casadevall, N., Rose, C., de Renzis, B., Peroni, E., Randi, Ml., Dumont, S., Ricordeau, I., Bezieau, S., Gardie, B., université de Bourgogne, LNC, Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Nantes (UN), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université catholique de Lille (UCL), Oncologie médicale [Hôpital Saint Vincent de Paul, Lille], Hôpital Saint-Vincent de Paul, Service d’Hématologie Biologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Department of Medicine (DIMED), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Nantes ( UN ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université catholique de Lille ( UCL ), and Service de thérapie cellulaire et hématologie clinique [CHU Clermont Ferrand]
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology
Abstract: IF 7.702; International audience
Published: 2017

10. A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma

Author: El-Habr, Elias A., Dubois, Luiz G., Burel-Vandenbos, Fanny, Bogeas, Alexandra, Lipecka, Joanna, Turchi, Laurent, Lejeune, François-Xavier, Coehlo, Paulo Lucas Cerqueira, Yamaki, Tomohiro, Wittmann, Bryan M., Fareh, Mohamed, Mahfoudhi, Emna, Janin, Maxime, Narayanan, Ashwin, Morvan-Dubois, Ghislaine, Schmitt, Charlotte, Verreault, Maité, Oliver, Lisa, Sharif, Ariane, Pallud, Johan, Devaux, Bertrand, Puget, Stéphanie, Korkolopoulou, Penelope, Varlet, Pascale, Ottolenghi, Chris, Plo, Isabelle, Moura-Neto, Vivaldo, Virolle, Thierry, Chneiweiss, Hervé, Junier, Marie-Pierre, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Instituto Estadual do cerebro Paulo Niemeyer, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service de pathologie, Centre Hospitalier Universitaire de Nice (CHU Nice), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Metabolon, Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie métabolique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Université Paris Descartes - Paris 5 (UPD5), Department of Paediatric Neurosurgery, Necker Enfants Malades Hospital, Paris, France., Department of Haematopathology, National and Kapodistrian University of Athens, Laikon General Hospital, Service de neuropathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Sainte-Anne, Hématopoïèse normale et pathologique (U1170 Inserm), This work was supported by La Ligue nationale contre le cancer (Equipe Labellisée LIGUE 2013, Equipe Labelisée LIGUE 2016 HC/MPJ), Institut National du Cancer (INCa 2012-1-PLBIO-07-INSERM-1, HC/MPJ), Cancéropole Région Ile-de-France (EAE and AB fellowships), CAPES/COFECUB (Coordination pour le perfectionnement du personnel de l’enseignement supérieur/Comité français d’evaluation de la coopération universitaire et scientifique avec le Brésil, VMN and LGD fellowship), Fundação Ary Frauzino para o Câncer (LGD fellowship), and Neurosurgeon college of Chiba prefecture, Japan (TY fellowship)., Neuroscience Paris Seine ( NPS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie Valrose ( IBV ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ), CHU Nice, Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing ( B2A ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Gustave Roussy ( IGR ) -Université Paris-Sud - Paris 11 ( UP11 ), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Sainte-Anne, Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Sainte-Anne, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Centre de Psychiatrie et Neurosciences (U894), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, National and Kapodistrian University of Athens (NKUA), and Bernardo, Elizabeth
Subjects: Male, Carcinogenesis, Clinical Neurology, Hydroxybutyrates, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Brain cancer, Pathology and Forensic Medicine, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Cellular and Molecular Neuroscience, GABA, [SDV.CAN] Life Sciences [q-bio]/Cancer, Animals, Humans, ALDH5A1, Child, gamma-Aminobutyric Acid, Aged, Cell Proliferation, Original Paper, Valproate, Cell Death, Brain Neoplasms, Cancer stem cell, Brain, Glioma, Middle Aged, 5-hmC, Child, Preschool, Neoplastic Stem Cells, DIPG, Female, Succinate-Semialdehyde Dehydrogenase, Neoplasm Transplantation
Abstract: Cell populations with differing proliferative, stem-like and tumorigenic states co-exist in most tumors and especially malignant gliomas. Whether metabolic variations can drive this heterogeneity by controlling dynamic changes in cell states is unknown. Metabolite profiling of human adult glioblastoma stem-like cells upon loss of their tumorigenicity revealed a switch in the catabolism of the GABA neurotransmitter toward enhanced production and secretion of its by-product GHB (4-hydroxybutyrate). This switch was driven by succinic semialdehyde dehydrogenase (SSADH) downregulation. Enhancing GHB levels via SSADH downregulation or GHB supplementation triggered cell conversion into a less aggressive phenotypic state. GHB affected adult glioblastoma cells with varying molecular profiles, along with cells from pediatric pontine gliomas. In all cell types, GHB acted by inhibiting α-ketoglutarate-dependent Ten–eleven Translocations (TET) activity, resulting in decreased levels of the 5-hydroxymethylcytosine epigenetic mark. In patients, low SSADH expression was correlated with high GHB/α-ketoglutarate ratios, and distinguished weakly proliferative/differentiated glioblastoma territories from proliferative/non-differentiated territories. Our findings support an active participation of metabolic variations in the genesis of tumor heterogeneity. Electronic supplementary material The online version of this article (doi:10.1007/s00401-016-1659-5) contains supplementary material, which is available to authorized users.
Published: 2016
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11. Transfer of functional microRNAs between glioblastoma and microvascular endothelial cells through gap junctions

Author: Eric Solary, Jonathan Boucher, Nicolas Pernet, Carmen Garrido, Dominique Thuringer, Gaëtan Jego, Laurent Cronier, Arlette Hammann, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Université de Poitiers-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Signalisation et Transports Ioniques Membranaires ( STIM ), Université de Poitiers-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL )
Subjects: 0301 basic medicine, Survival, Angiogenesis, Gene Expression, Connexin, Expression, Cell Communication, RNA Transport, Microrna, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Invasion, U87, Cancer, Tumor, Neovascularization, Pathologic, Progression, Gap junction, Gap Junctions, Brain, Tubulogenesis, Cell biology, medicine.anatomical_structure, Oncology, Gap Junction, Research Paper, medicine.drug, Cell type, Endothelium, Carbenoxolone, Glioma-Cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, United-States, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Cell Line, Tumor, microRNA, medicine, Humans, neoplasms, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Endothelial Cells, nervous system diseases, body regions, MicroRNAs, 030104 developmental biology, Intercellular Communication, Immunology, Glioblastoma
Abstract: IF 5.008; International audience; Extensive invasion and angiogenesis are hallmark features of malignant glioblastomas. Here, we co-cultured U87 human glioblastoma cells and human microvascular endothelial cells (HMEC) to demonstrate the exchange of microRNAs that initially involve the formation of gap junction communications between the two cell types. The functional inhibition of gap junctions by carbenoxolone blocks the transfer of the anti-tumor miR-145-5p from HMEC to U87, and the transfer of the pro-invasive miR-5096 from U87 to HMEC. These two microRNAs exert opposite effects on angiogenesis in vitro. MiR-5096 was observed to promote HMEC tubulogenesis, initially by increasing Cx43 expression and the formation of heterocellular gap junctions, and secondarily through a gap-junction independent pathway. Our results highlight the importance of microRNA exchanges between tumor and endothelial cells that in part involves the formation of functional gap junctions between the two cell types.
Published: 2016
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12. P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis

Author: Jiajia Pan, Laurent Debussche, Philippe Rameau, Salem Abbes, Hana Raslova, Anita Roy, Najet Debili, Caroline Marty, William Vainchenker, Isabelle Plo, Emna Mahfoudhi, Larissa Lordier, Yunhua Chang, Lydia Roy, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'hématologie moléculaire et cellulaire (LR11IPT07), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Plateforme imagerie et cytométrie (PFIC), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sanofi Research & Development - Oncology, This work was supported by grants from ANR(ANR-blanc thrombocytosis and ANR-13-JSV1-0007-02)(IP, VW) and from the Ligue Nationale contre le Cancer(WV, HR équipe labellisée 2012, 2016). Labex GR-Ex (IP,WV) is funded by the program 'Investissements d’avenir'.EM was supported bygrants from Sanofi., ANR-11-BSV1-0001,Thrombocytosis,Mécanismes des thrombocytoses acquises et familiales(2011), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pasteur Tunis, Institut, BLANC - Mécanismes des thrombocytoses acquises et familiales - - Thrombocytosis2011 - ANR-11-BSV1-0001 - BLANC - VALID, Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire d'hématologie moléculaire et cellulaire ( LR11IPT07 ), Institut Pasteur de Tunis-Réseau International des Instituts Pasteur ( RIIP ), Plateforme imagerie et cytométrie ( PFIC ), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse ( AMMICa ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), ANR-11-BSV1-0001,Thrombocytosis,Mécanismes des thrombocytoses acquises et familiales ( 2011 ), Institut Pasteur de Tunis - Réseau International des Instituts Pasteur (RIIP), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11) - Institut Gustave Roussy (IGR) - Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université de Bordeaux (UB), Institut de physiologie et biologie cellulaires (IPBC), Université de Poitiers - Centre National de la Recherche Scientifique (CNRS), Laboratory of Molecular and Cellular Hematology, Institut Pasteur de Tunis - Réseau International des Instituts Pasteur (RIIP) - Institut Pasteur de Tunis - Réseau International des Instituts Pasteur (RIIP), Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), and Laboratoire d'Excellence du Globule Rouge, Villejuif, France
Subjects: 0301 basic medicine, p53, Programmed cell death, Indoles, Time Factors, Tumor suppressor gene, Cell Survival, DNA repair, [SDV]Life Sciences [q-bio], Antigens, CD34, Transfection, Piperazines, Thrombopoiesis, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Humans, Spiro Compounds, Progenitor cell, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Megakaryopoiesis, progenitors, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Dose-Response Relationship, Drug, biology, [ SDV ] Life Sciences [q-bio], Imidazoles, apoptosis, Proto-Oncogene Proteins c-mdm2, Nutlin, Hematopoietic Stem Cells, Thrombocytopenia, 3. Good health, [SDV] Life Sciences [q-bio], Haematopoiesis, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, MDM2 inhibitors, Cancer research, biology.protein, Mdm2, RNA Interference, Tumor Suppressor Protein p53, megakaryopoiesis, Signal Transduction, Research Paper
Abstract: International audience; TP53 also known as p53 is a tumor suppressor gene mutated in a variety of cancers. P53 is involved in cell cycle, apoptosis and DNA repair mechanisms and is thus tightly controlled by many regulators. Recently, strategies to treat cancer have focused on the development of MDM2 antagonists to induce p53 stabilization and restore cell death in p53 non-mutated cancers. However, some of these molecules display adverse effects in patients including induction of thrombocytopenia. In the present study, we have explored the effect of SAR405838 not only on human megakaryopoiesis but also more generally on hematopoiesis. We compared its effect to MI-219 and Nutlin, which are less potent MDM2 antagonists than SAR405838. We found that all these compounds induce a deleterious effect on all types of hematopoietic progenitors, as well as on erythroid and megakaryocytic differentiation. Moreover, they inhibit both early and late stages of megakaryopoiesis including ploidization and proplatelet formation. In conclusion, MDM2 antagonists induced a major hematopoietic defect in vitro as well as an inhibition of all stages of megakaryopoiesis that may account for in vivo thrombocytopenia observed in treated patients.
Published: 2016
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13. Erythrocyte-derived microvesicles induce arterial spasms in JAK2V617F myeloproliferative neoplasm

Author: Poisson, Johanne, Tanguy, Marion, Davy, Hortense, Camara, Fatoumata, El Mdawar, Marie-Belle, Kheloufi, Marouane, Dagher, Tracy, Devue, Cécile, Lasselin, Juliette, Plessier, Aurélie, Merchant, Salma, Blanc-Brude, Olivier, Souyri, Michèle, Mougenot, Nathalie, Dingli, Florent, Loew, Damarys, Hatem, Stephane N., James, Chloé, Villeval, Jean-Luc, Boulanger, Chantal M., Rautou, Pierre-Emmanuel, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Gériatrie [Hôpital Européen Georges Pompidou, Paris], Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Hépatologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de référence des Maladies Vasculaires du Foie [Paris] (FILFOIE), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Phénotypage du petit animal (UMS28), Sorbonne Université (SU), Laboratoire de Spectrométrie de Masse Protéomique, Institut Curie [Paris], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), Laboratoire d'Hématologie, Hôpital Haut Lévêque CHU de Bordeaux, Pessac, CHU Bordeaux [Bordeaux], This work was supported by the Agence Nationale pour la Recherche (ANR 14 CE35 0022 03/ JAK-POT) and J.P by the 'poste accueil INSERM'. The proteomic plateform is supported by 'Région Ile-de-France' (2013-2-EML-02-ICR-1) and Fondation pour la Recherche Médicale (DGE20121125630) grants (to D.L.)., Poisson, Johanne, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Simvastatin, Erythrocytes, Cardiology, Aorta, Thoracic, Mice, Transgenic, In Vitro Techniques, Antioxidants, Mice, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cell-Derived Microparticles, Animals, Humans, Cancer, Myeloproliferative Disorders, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Janus Kinase 2, Cardiovascular disease, endothelial cells, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Femoral Artery, Mice, Inbred C57BL, Oxidative Stress, Cardiovascular Diseases, Vasoconstriction, Gain of Function Mutation, Research Article
Abstract: International audience; Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPN). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPN suggests that vascular function is altered. Consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice, resulting from disturbed endothelial nitric oxide pathway and increased endothelial oxidative stress. This response was reproduced in wild-type mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for microvesicles effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes supressed their effect on oxidative stress. Antioxidants, such as simvastatin and N-acetyl-cysteine, improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPN are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears as promising therapeutic strategy in this setting.
Published: 2020
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14. Dual role of EZH2 in megakaryocyte differentiation

Author: Rachel Petermann, Bruno Cassinat, Mathieu Vieira, Marie Cambot, William Vainchenker, Monika Wittner, Isabelle Plo, Philippe Dessen, Hana Raslova, Mira El Khoury, Najet Debili, Francesca Basso-Valentina, Valérie Edmond, Iléana Antony-Debré, Salwa BenAbdoulahab, Brahim Arkoun, Stefania Mazzi, Philippe Rameau, Virginie Dufour, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Plateforme de Bioinformatique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Microbiologie : Risques Infectieux, Université de Rennes (UR)-CHU Pontchaillou [Rennes]-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes - UFR d'Odontologie (UR Odontologie), Université de Rennes (UR)-Université de Rennes (UR), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Gamétogenèse et Qualité du Gamète - ULR 4308 (GQG), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Lille, Institut National de la Transfusion Sanguine [Paris] (INTS), Service de Biologie Cellulaire [Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Faculté de Chirurgie Dentaire de Rennes-Faculté d'Odontologie-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP)
Subjects: Blood Platelets, Megakaryocyte differentiation, [SDV]Life Sciences [q-bio], Immunology, macromolecular substances, Biochemistry, Thrombopoiesis, Small hairpin RNA, Mice, 03 medical and health sciences, 0302 clinical medicine, Megakaryocyte, Downregulation and upregulation, medicine, Animals, Humans, Enhancer of Zeste Homolog 2 Protein, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Gene knockdown, biology, Chemistry, Kinase, Cell Biology, Hematology, Platelets and Thrombopoiesis, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, biology.protein, RNA Interference, Transcriptome, PRC2, Megakaryocytes, Chromatin immunoprecipitation
Abstract: EZH2, the enzymatic component of PRC2, has been identified as a key factor in hematopoiesis. EZH2 loss-of-function mutations have been found in myeloproliferative neoplasms, particularly in myelofibrosis, but the precise function of EZH2 in megakaryopoiesis is not fully delineated. Here, we show that EZH2 inhibition by small molecules and short hairpin RNA induces megakaryocyte (MK) commitment by accelerating lineage marker acquisition without change in proliferation. Later in differentiation, EZH2 inhibition blocks proliferation and polyploidization and decreases proplatelet formation. EZH2 inhibitors similarly reduce MK polyploidization and proplatelet formation in vitro and platelet levels in vivo in a JAK2V617F background. In transcriptome profiling, the defect in proplatelet formation was associated with an aberrant actin cytoskeleton regulation pathway, whereas polyploidization was associated with an inhibition of expression of genes involved in DNA replication and repair and an upregulation of cyclin-dependent kinase inhibitors, particularly CDKN1A and CDKN2D. The knockdown of CDKN1A and to a lesser extent CDKN2D could partially rescue the percentage of polyploid MKs. Moreover, H3K27me3 and EZH2 chromatin immunoprecipitation assays revealed that CDKN1A is a direct EZH2 target and CDKN2D expression is not directly regulated by EZH2, suggesting that EZH2 controls MK polyploidization directly through CDKN1A and indirectly through CDKN2D.
Published: 2021
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15. Common Pathological Mechanisms and Risk Factors for Alzheimer’s Disease and Type-2 Diabetes: Focus on Inflammation

Author: Mohamed Haddad, Camelia Benlabiod, Emmanuel Moyse, Charles Ramassamy, Slavica Krantic, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Communication Cellulaire en Biologie de la Reproduction, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), INRS-Centre Armand-Frappier Sante Biotechnologie, Pathologies biliaires, fibrose et cancer du foie (Inserm UMR_S 938), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Foundation Armand-Frappier (Laval, Qc, Canada) Conseil Franco-Quebecois de Cooperation Universitaire (CFQCU) 2018/074
Subjects: Male, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, microglia, Inflammation, Type 2 diabetes, Disease, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Alzheimer Disease, Risk Factors, insulin resistance, Diabetes mellitus, medicine, Humans, Pancreas, vasculopathy, Pathological, Neuroinflammation, Aged, 030304 developmental biology, 0303 health sciences, business.industry, advanced glycation end products, Amyloidosis, Brain, medicine.disease, cytokines, 3. Good health, Diabetes Mellitus, Type 2, Neurology, innate immune response, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], hyperglycemia, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Background :Diabetes is considered as a risk factor for Alzheimer’s Disease, but it is yet unclear whether this pathological link is reciprocal. Although Alzheimer’s disease and diabetes appear as entirely different pathological entities affecting the Central Nervous System and a peripheral organ (pancreas), respectively, they share a common pathological core. Recent evidence suggests that in the pancreas in the case of diabetes, as in the brain for Alzheimer’s Disease, the initial pathological event may be the accumulation of toxic proteins yielding amyloidosis. Moreover, in both pathologies, amyloidosis is likely responsible for local inflammation, which acts as a driving force for cell death and tissue degeneration. These pathological events are all inter-connected and establish a vicious cycle resulting in the progressive character of both pathologies.Objective:To address the literature supporting the hypothesis of a common pathological core for both diseases.Discussion:We will focus on the analogies and differences between the disease-related inflammatory changes in a peripheral organ, such as the pancreas, versus those observed in the brain. Recent evidence suggesting an impact of peripheral inflammation on neuroinflammation in Alzheimer’s disease will be presented.Conclusion:We propose that it is now necessary to consider whether neuroinflammation in Alzheimer’s disease affects inflammation in the pancreas related to diabetes.
Published: 2019
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16. CABLES1 Deficiency Impairs Quiescence and Stress Responses of Hematopoietic Stem Cells in Intrinsic and Extrinsic Manners

Author: Viviane Baral, Liang He, Mallorie Depond, Fawzia Louache, Florian Beghi, Yanyan Zhang, Virginie Joulin, M. Wittner, Patrick Gonin, Adlen Foudi, Bo R. Rueda, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Hématopoïèse normale et pathologique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Modèles de Cellules Souches Malignes et Thérapeutiques, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Lipopolysaccharides, 0301 basic medicine, Aging, hematopoietic niches, Antigens, CD34, Biochemistry, Mice, 0302 clinical medicine, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], RNA, Small Interfering, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, lcsh:R5-920, p21, Hematopoietic Stem Cell Transplantation, hematopoietic stem cell homeostasis, Cell biology, Haematopoiesis, medicine.anatomical_structure, cell cycle, RNA Interference, Fluorouracil, Stem cell, mesenchymal stromal cells, lcsh:Medicine (General), Cyclin-Dependent Kinase Inhibitor p21, Bone Marrow Cells, Biology, Article, 03 medical and health sciences, Cyclins, Genetics, medicine, Animals, Humans, Peripheral blood cell, Progenitor cell, Cell Proliferation, Hematopoietic stem cell homeostasis, Mesenchymal stem cell, Cell Cycle Checkpoints, Cell Biology, Hematopoietic Stem Cells, Hematopoiesis, Mice, Inbred C57BL, Transplantation, 030104 developmental biology, lcsh:Biology (General), CABLES1, Bone marrow, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Summary Bone marrow (BM) niche cells help to keep adult hematopoietic stem cells (HSCs) in a quiescent state via secreted factors and induction of cell-cycle inhibitors. Here, we demonstrate that the adapter protein CABLES1 is a key regulator of long-term hematopoietic homeostasis during stress and aging. Young mice lacking Cables1 displayed hyperproliferation of hematopoietic progenitor cells. This defect was cell intrinsic, since it was reproduced in BM transplantation assays using wild-type animals as recipients. Overexpression and short hairpin RNA-mediated depletion of CABLES1 protein resulted in p21Cip/waf up- and downregulation, respectively. Aged mice lacking Cables1 displayed abnormalities in peripheral blood cell counts accompanied by a significant reduction in HSC compartment, concomitant with an increased mobilization of progenitor cells. In addition, Cables1−/− mice displayed increased sensitivity to the chemotherapeutic agent 5-fluorouracil due to an abnormal microenvironment. Altogether, our findings uncover a key role for CABLES1 in HSC homeostasis and stress hematopoiesis., Graphical Abstract, Highlights • CABLES1 is expressed in immature hematopoietic progenitor cells and niche cells • CABLES1 in an intrinsic negative cell-cycle regulator of hematopoietic progenitor cells • CABLES1 regulates p21Cip/waf protein levels • The abnormal stress responses of Cables1−/− HSC during aging are niche cell dependent, Maintenance of hematopoietic stem cell quiescence is crucial for homeostasis. Using mutant mice and cross-transplant experiments, Louache and colleagues show that the adapter protein CABLES1 is required for stem cell quiescence under transplantation and regulates p21Cip/waf protein level. In addition, CABLES1 is a niche-based regulator of hematopoietic stem cell responses to proliferative stress and during aging.
Published: 2019
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17. A Recurrent Activating Missense Mutation in Waldenström Macroglobulinemia Affects the DNA Binding of the ETS Transcription Factor SPI1 and Enhances Proliferation

Author: Nathalie Droin, Philippe Rameau, Philippe Dessen, Florence Nguyen-Khac, Bilyana Stoilova, Elena Mylonas, Marine Armand, Damien Roos-Weil, Olivier Bernard, Els Verhoeyen, Paresh Vyas, Said Aoufouchi, Marlen Metzner, Françoise Pflumio, Frédéric Charlotte, Vincent Ribrag, Diane Lara, Olivier Elemento, Pierre Morel, Eric Durot, Cécile Hérate, Pascale Cornillet-Lefebvre, Véronique Della-Valle, Hussein Ghamlouch, Virginie Ropars, Frederik Damm, Nabih Azar, Christel Guillouf, François-Loïc Cosset, Camille Decaudin, Valérie Camara-Clayette, M'Boyba Diop, Veronique Leblond, Thomas Mercher, Jean-Baptiste Charbonnier, Rima Haddad, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Enveloppe Nucléaire, Télomères et Réparation de l’ADN (INTGEN), Département Biochimie, Biophysique et Biologie Structurale (B3S), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Department of Haematology, Haemostasis, Oncology and Stem Cell Transplantation (MHH), Hannover Medical School [Hannover] (MHH), CEA Direction des Sciences du Vivant (CEA/DSV), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), The Weatherall Institute of Molecular Medicine, University of Oxford [Oxford], Weill Medical College of Cornell University [New York], Institut Gustave Roussy (IGR), Plateforme de Bioinformatique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de recherche translationnelle (Labo RT), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Département d'hématologie [Gustave Roussy], Laboratoire d'hématologie, Centre Hospitalier Universitaire de Reims (CHU Reims), Plateforme imagerie et cytométrie (PFIC), Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Brigham and Women's Hospital [Boston], Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ligue Nationnale Contre le Cancer, Centre de Recherche et d'Etude en Droit et Science Politique (CREDESPO), Université de Bourgogne (UB), University of Oxford, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and École Pratique des Hautes Études (EPHE)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Mutation, Missense, lymphoma, Biology, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Mutant protein, Proto-Oncogene Proteins, spi-1/pu.1, pu.1, Animals, Humans, somatic mutation, Nucleotide Motifs, Lenalidomide, Transcription factor, mouse, Cell Proliferation, cll, B-Lymphocytes, Binding Sites, SPI1, Base Sequence, Proto-Oncogene Proteins c-ets, Point mutation, ETS transcription factor family, Promoter, Azepines, Triazoles, Cell biology, cell differentiation, 030104 developmental biology, Gene Expression Regulation, Oncology, 030220 oncology & carcinogenesis, Myeloid Differentiation Factor 88, Trans-Activators, acute myeloid-leukemia, Waldenstrom Macroglobulinemia, Transcription Factor Gene, Protein Binding, Transcription Factors
Abstract: The ETS-domain transcription factors divide into subfamilies based on protein similarities, DNA-binding sequences, and interaction with cofactors. They are regulated by extracellular clues and contribute to cellular processes, including proliferation and transformation. ETS genes are targeted through genomic rearrangements in oncogenesis. The PU.1/SPI1 gene is inactivated by point mutations in human myeloid malignancies. We identified a recurrent somatic mutation (Q226E) in PU.1/SPI1 in Waldenström macroglobulinemia, a B-cell lymphoproliferative disorder. It affects the DNA-binding affinity of the protein and allows the mutant protein to more frequently bind and activate promoter regions with respect to wild-type protein. Mutant SPI1 binding at promoters activates gene sets typically promoted by other ETS factors, resulting in enhanced proliferation and decreased terminal B-cell differentiation in model cell lines and primary samples. In summary, we describe oncogenic subversion of transcription factor function through subtle alteration of DNA binding leading to cellular proliferation and differentiation arrest. Significance: The demonstration that a somatic point mutation tips the balance of genome-binding pattern provides a mechanistic paradigm for how missense mutations in transcription factor genes may be oncogenic in human tumors. This article is highlighted in the In This Issue feature, p. 681
Published: 2019
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18. Regulation of globin-heme balance in Diamond-Blackfan anemia by HSP70/GATA1

Author: Rio, Sarah, Gastou, Marc, Karboul, Narjesse, Derman, Raphaёl, Suriyun, Thunwarat, Manceau, Hana, Leblanc, Thierry, El Benna, Jamel, Schmitt, Caroline, Azouzi, Slim, Larghero, Jérôme, Karim, Zoubida, Macias-Garcia, Alejandra, Chen, Jane-Jane, Puy, Hervé, Gouya, Laurent, Mohandas, Narla, Da Costa, Lydie, Sibon, David, Coman, Tereza, Rossignol, Julien, Lamarque, Mathilde, Kosmider, Olivier, Bayard, Elisa, Fouquet, Guillemette, Rignault, Rachel, Topçu, Selin, Bonneau, Pierre, Bernex, Florence, Dussiot, Michaël, Deroy, Kathy, Laurent, Laetitia, Callebert, Jacques, Launay, Jean-Marie, Georgin-Lavialle, Sophie, COURTOIS, genevieve, Maroteaux, Luc, Vaillancourt, Cathy, Fontenay, Michaela, Hermine, Olivier, Côté, Francine, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de recherche translationnelle, Institut Curie [Paris], Jet Propulsion Laboratory (JPL), NASA-California Institute of Technology (CALTECH), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Français des Porphyries, Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Biotherapie - Saint Louis ((CIC-BT 301)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Génétique et Centre de Référence Maladies Rares Syndrome de Marfan et pathologies apparentées (AP HP, hôpital Bichat), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Red Cell Physiology Laboratory [New York, USA], New York Blood Center, AP-HP, Service d'Hématologie Biologique, Hôpital Robert-Debré, Service d'hématologie-oncologie adultes, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Field Neurosciences Laboratory for Restorative Neurology [Mount Pleasant, MI, USA] (Program in Neuroscience ), Central Michigan University (CMU), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie biologique, Hôpital Cochin [AP-HP], Université Sorbonne Paris Cité (USPC), Hôpital Claude Huriez [Lille], CHU Lille, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Mathématiques de Toulouse UMR5219 (IMT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Departement /u661 : Endocrinologie, Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Biochimie et Biologie Moleculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Service de biochimie et biologie moléculaire, IFR139-Hôpital Lariboisière-Fernand-Widal [APHP], Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut du Fer à Moulin, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Robert Debré, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Hopital Saint-Louis [AP-HP] (AP-HP), Massachusetts Institute of Technology (MIT), COURTOIS, genevieve, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR139, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)
Subjects: Male, Ribosomal Proteins, Cellular differentiation, Immunology, Haploinsufficiency, Heme, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biochemistry, Small hairpin RNA, 03 medical and health sciences, chemistry.chemical_compound, Red Cells, Iron, and Erythropoiesis, 0302 clinical medicine, Erythroid Cells, hemic and lymphatic diseases, medicine, Humans, GATA1 Transcription Factor, HSP70 Heat-Shock Proteins, Globin, RNA, Small Interfering, Diamond–Blackfan anemia, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Anemia, Diamond-Blackfan, Cell Proliferation, 030304 developmental biology, 0303 health sciences, Chemistry, Cell growth, Infant, Newborn, Infant, Cell Differentiation, GATA1, Cell Biology, Hematology, Prognosis, medicine.disease, Phenotype, Globins, 3. Good health, Cell biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, Mutation, Female, Follow-Up Studies
Abstract: Diamond-Blackfan anemia (DBA) is a congenital erythroblastopenia that is characterized by a blockade in erythroid differentiation related to impaired ribosome biogenesis. DBA phenotype and genotype are highly heterogeneous. We have previously identified 2 in vitro erythroid cell growth phenotypes for primary CD34+ cells from DBA patients and following short hairpin RNA knockdown of RPS19, RPL5, and RPL11 expression in normal human CD34+ cells. The haploinsufficient RPS19 in vitro phenotype is less severe than that of 2 other ribosomal protein (RP) mutant genes. We further documented that proteasomal degradation of HSP70, the chaperone of GATA1, is a major contributor to the defect in erythroid proliferation, delayed erythroid differentiation, increased apoptosis, and decreased globin expression, which are all features of the RPL5 or RPL11 DBA phenotype. In the present study, we explored the hypothesis that an imbalance between globin and heme synthesis may be involved in pure red cell aplasia of DBA. We identified disequilibrium between the globin chain and the heme synthesis in erythroid cells of DBA patients. This imbalance led to accumulation of excess free heme and increased reactive oxygen species production that was more pronounced in cells of the RPL5 or RPL11 phenotype. Strikingly, rescue experiments with wild-type HSP70 restored GATA1 expression levels, increased globin synthesis thereby reducing free heme excess and resulting in decreased apoptosis of DBA erythroid cells. These results demonstrate the involvement of heme in DBA pathophysiology and a major role of HSP70 in the control of balanced heme/globin synthesis.
Published: 2019
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19. Lyl-1 marks and regulates primitive macrophages and microglia development

Author: Wang, Shoutang, Ren, Deshan, Kaushik, Anna-Lila, Matherat, Gabriel, Lécluse, Yann, Filipp, Dominik, Vainchenker, William, Raslova, Hana, Plo, Isabelle, Godin, Isabelle, Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Hématopoïèse normale et pathologique (U1170 Inserm), and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis
Abstract: During ontogeny, resident macrophages (MΦs) of the nervous system emerge from haematopoietic stem cell-independent progenitors originating in the Yolk Sac (YS), so that factors impairing YS MΦ development may lead to neurodevelopmental disorders resulting from defective brain resident MΦ.; Here we show that Lyl-1, a bHLH transcription factor related to Scl/Tal-1, marks primitive macrophage (MΦ Prim ) progenitors in the YS. Transcriptomic analysis of YS MΦ progenitors indicated that MΦ Prim progenitors present at embryonic day (E) 9 are clearly distinct from those present at E10. Lyl-1 bHLH disruption led to an increased production and a defective differentiation of MΦ Prim progenitors. These differentiation defects were associated with profound modifications of the expression of genes involved in embryonic patterning and neurodevelopment. They also induced a reduced production of mature MΦ/microglia in the early brain, as well as a transient reduction of the microglia pool at midgestation and in the new-born.; We thus identify Lyl-1 as a critical regulator of MΦ Prim and microglia development, which disruption may impair organogenesis, including neurodevelopment processes.; Key points: 1-Lyl-1 expression marks yolk sac macrophages and brain macrophage/microglia/BAM. 2-Lyl-1 deficiency impairs primitive macrophage development and leads to the up-regulation of genes involved in embryo patterning. 3-Lyl-1-expressing primitive macrophages have an immuno-modulatory phenotype. 4-Lyl-1 deficiency impairs microglia development and the expression of genes involved in neuro-development.
Published: 2020

20. JAK2V617F myeloproliferative neoplasm eradication by a novel interferon/arsenic therapy involves PML

Author: Dagher, Tracy, Maslah, Nabih, Edmond, Valérie, Cassinat, Bruno, Vainchenker, William, Giraudier, Stéphane, Pasquier, Florence, Niwa-Kawakita, Michiko, Lallemand-Breitenbach, Valérie, Plo, Isabelle, Kiladjian, Jean-Jacques, Villeval, Jean-Luc, de Thé, Hugues, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), France Intergroupe des Syndromes Myeloproliferatifs (FMI Paris), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Biologie Cellulaire [AP-HP Hôpital Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Université Paris Cité (UPCité), Université de Lille, Département de neurologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Collège de France - Chaire Oncologie cellulaire et moléculaire, and Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; Interferon α (IFNα) is used to treat JAK2 V617F-driven myeloproliferative neoplasms (MPNs) but rarely clears the disease. We investigated the IFNα mechanism of action focusing on PML, an interferon target and key senescence gene whose targeting by arsenic trioxide (ATO) drives eradication of acute promyelocytic leukemia. ATO sharply potentiated IFNα-induced growth suppression of JAK2 V617F patient or mouse hematopoietic progenitors, which required PML and was associated with features of senescence. In a mouse MPN model, combining ATO with IFNα enhanced and accelerated responses, eradicating MPN in most mice by targeting disease-initiating cells. These results predict potent clinical efficacy of the IFNα+ATO combination in patients and identify PML as a major effector of therapy, even in malignancies with an intact PML gene. .
Published: 2020
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21. Turning off NADPH oxidase-2 by impeding p67phox activation in infected mouse macrophages reduced viral entry and inflammation

Author: Edna Bechor, Pierre Adenot, Jasmina Vidic, Nicolas Bertho, Vijay M. Khedkar, Nathalie Lejal, Stéphanie Solier, Edgar Pick, Sandrine Truchet, Edwige Bouguyon, Anny Slama-Schwok, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Université Paris Saclay (COmUE), Sackler Faculty of Medicine, Biologie du Développement et Reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Plateforme MIMA2, Institut Gustave Roussy (IGR), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-14-CE09-0017-02, Bioasia 35976PH
Subjects: 0301 basic medicine, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], viruses, Biophysics, Inflammation, Endocytosis, Biochemistry, 03 medical and health sciences, Immune system, Viral entry, medicine, NADPH oxidase‑2, Molecular Biology, NADPH oxidase, 030102 biochemistry & molecular biology, biology, Chemistry, Activator (genetics), Confocal imaging, 3. Good health, Cell biology, Protein-protein and protein-ligand interactions, Kinetics, Influenza A virus entry, 030104 developmental biology, cardiovascular system, biology.protein, Tumor necrosis factor alpha, medicine.symptom, Intracellular, circulatory and respiratory physiology
Abstract: International audience; Background: Targeting cells of the host immune system is a promising approach to fight against Influenza A virus (IAV) infection. Macrophage cells use the NADPH oxidase-2 (NOX2) enzymatic complex as a first line of defense against pathogens by generating superoxide ions O-2(-) and releasing H2O2. Herein, we investigated whether targeting membrane-embedded NOX2 decreased IAV entry via raft domains and reduced inflammation in infected macrophages. Methods: Confocal microscopy and western blots monitored levels of the viral nucleoprotein NP and p67(Phox), NOX2 activator subunit, Elisa assays quantified TNF-alpha levels in LPS or IAV-activated mouse or porcine alveolar macrophages pretreated with a fluorescent NOX inhibitor, called nanoshutter NS1. Results: IAV infection in macrophages promoted p67(Phox) translocation to the membrane, rafts clustering and activation of the NOX2 complex at early times. Disrupting rafts reduced intracellular viral NP. NS1 markedly reduced raft clustering and viral entry by binding to the C-terminal of NOX2 also characterized in vitro. NS1 decrease of TNF-a release depended on the cell type. Conclusion: NOX2 participated in IAV entry and raft-mediated endocytosis. NOX2 inhibition by NS1 reduced viral entry. NS1 competition with p67(Phox) for NOX2 binding shown by in silico models and cell-free assays was in agreement with NS1 inhibiting p67(Phox) translocation to membrane-embedded NOX2 in mouse and porcine macrophages. General significance: We introduce NS1 as a compound targeting NOX2, a critical enzyme controlling viral levels and inflammation in macrophages and discuss the therapeutic relevance of targeting the C-terminal of NADPH oxidases by probes like NS1 in viral infections.
Published: 2018
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22. B-cell tumor development in Tet2-deficient mice

Author: Cécile K. Lopez, Philippe Dessen, Michaela Fontenay, Hussein Ghamlouch, Patrycja Pawlikowska, Olivier Bernard, Cyril Quivoron, Véronique Saada, Enguerran Mouly, Laurianne Scourzic, Said Aoufouchi, Ivo P. Touw, M'Boyba Diop, Damien Roos-Weil, Thomas Mercher, Véronique Della-Valle, Différenciation des cellules B, hémopathies, lymphoïdes et déficit de l'immunité humorale, Université Paris Diderot - Paris 7 ( UPD7 ), Génétique des hémopathies humaines ( EMI 210 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Gustave Roussy ( IGR ), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunology-Hematology, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Génomes et cancer ( GC (FRE2939) ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Développement du Systeme Immunitaire, Liquides Ioniques et Interfaces Chargées ( LI2C ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -ESPCI ParisTech-Centre National de la Recherche Scientifique ( CNRS ), and Hematology
Subjects: 0301 basic medicine, APOBEC, Lymphoma, B-Cell, Myeloid, Genotype, Cell Survival, Chronic lymphocytic leukemia, Receptors, Antigen, B-Cell, Biology, Dioxygenases, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 03 medical and health sciences, Proto-Oncogene Proteins, Leukemia, B-Cell, medicine, Animals, Genetic Predisposition to Disease, Alleles, Genetic Association Studies, B cell, Mice, Knockout, B-Lymphocytes, Lymphoid Neoplasia, breakpoint cluster region, Hematology, Flow Cytometry, medicine.disease, DNA-Binding Proteins, Leukemia, 030104 developmental biology, DNA demethylation, medicine.anatomical_structure, Mutation, Cancer research, CD5, Biomarkers
Abstract: International audience; The TET2 gene encodes an α-ketoglutarate-dependent dioxygenase able to oxidize 5-methylcytosine into 5-hydroxymethylcytosine, which is a step toward active DNA demethylation. TET2 is frequently mutated in myeloid malignancies but also in B- and T-cell malignancies. TET2 somatic mutations are also identified in healthy elderly individuals with clonal hematopoiesis. Tet2-deficient mouse models showed widespread hematological differentiation abnormalities, including myeloid, T-cell, and B-cell malignancies. We show here that, similar to what is observed with constitutive Tet2-deficient mice, B-cell-specific Tet2 knockout leads to abnormalities in the B1-cell subset and a development of B-cell malignancies after long latency. Aging Tet2-deficient mice accumulate clonal CD19+ B220low immunoglobulin M+ B-cell populations with transplantable ability showing similarities to human chronic lymphocytic leukemia, including CD5 expression and sensitivity to ibrutinib-mediated B-cell receptor (BCR) signaling inhibition. Exome sequencing of Tet2-/- malignant B cells reveals C-to-T and G-to-A mutations that lie within single-stranded DNA-specific activation-induced deaminase (AID)/APOBEC (apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like) cytidine deaminases targeted motif, as confirmed by the lack of a B-cell tumor in compound Tet2-Aicda-deficient mice. Finally, we show that Tet2 deficiency accelerates and exacerbates T-cell leukemia/lymphoma 1A-induced leukemogenesis. Together, our data establish that Tet2 deficiency predisposes to mature B-cell malignancies, which development might be attributed in part to AID-mediated accumulating mutations and BCR-mediated signaling.
Published: 2018
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23. Combined HAT/EZH2 modulation leads to cancer-selective cell death

Author: Valeria Cicatiello, Alfonso Baldi, Eva M. Janssen-Megens, Simon Heath, Olivier A. Bernard, Mariarosaria Conte, Edo Vellenga, Gianluca Sbardella, Alessandra Feoli, Antonello Mai, Francesca Petraglia, Concetta Ingenito, Bowon Kim, Valeria Belsito Petrizzi, Guoqiang Yi, Stefano Tomassi, Abhishek Singh, Angela Nebbioso, Ivo Gut, Paul Flicek, Albertus T. J. Wierenga, Marie-Laure Yaspo, Joost H.A. Martens, Hendrik G. Stunnenberg, Ivana Apicella, Lucia Scisciola, Sergio Valente, Ettore Novellino, Véronique Della Valle, Menotti Ruvo, Sandro De Falco, Amit Mandoli, Colin Logie, Vincenzo Carafa, Lucia Altucci, Università degli studi della Campania 'Luigi Vanvitelli', Radboud university [Nijmegen], Institut de Recherche Vétérinaire de Tunisie (IRVT), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Ospedale Umberto I, Istituto di Biofisica e Genetica 'Adriano Buzzati Traverso', Consiglio Nazionale delle Ricerche (CNR), Centro Nacional de Analisis Genomico [Barcelona] (CNAG), CNR – Istituto di Biostrutture e Bioimmagini, University Medical Center Groningen [Groningen] (UMCG), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Department of Medicinal Chemistry and Technologies, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Università degli studi di Napoli Federico II, Università degli Studi di Salerno (UNISA), Centro Nacional de Análisi Genómico (CNAG), Centro Nacional de Análisis Genómico, This work was supported by BLUEPRINT (282510), Programma VALERE: Vanvitelli per la Ricerca, the Italian-Flag Project-EPIGEN, PRIN-20152TE5PK, the Italian association against cancer (AIRC-17217), the Dutch Cancer Foundation (KWF kun 2011–4937) and Netherlands organization for Scientific Research (NWO-VIDI)., Petraglia, Francesca, Singh, Abhishek A., Carafa, Vincenzo, Nebbioso, Angela, Conte, Mariarosaria, Scisciola, Lucia, Valente, Sergio, Baldi, Alfonso, Mandoli, Amit, Petrizzi, Valeria Belsito, Ingenito, Concetta, De Falco, Sandro, Cicatiello, Valeria, Apicella, Ivana, Janssen-Megens, Eva M., Kim, Bowon, Yi, Guoqiang, Logie, Colin, Heath, Simon, Ruvo, Menotti, Wierenga, Albertus T. J., Flicek, Paul, Yaspo, Marie Laure, Della Valle, Veronique, Bernard, Olivier, Tomassi, Stefano, Novellino, Ettore, Feoli, Alessandra, Sbardella, Gianluca, Gut, Ivo, Vellenga, Edo, Stunnenberg, Hendrik G., Mai, Antonello, Martens, Joost H. A., Altucci, Lucia, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: 0301 basic medicine, acetylation, apoptosis, cancer, epigenetics, methylation, oncology, Programmed cell death, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, In vivo, medicine, Molecular Biology, business.industry, Cancer, Epigenetics, Apoptosis, Acetylation, Methylation, EZH2, Apoptosi, Epigenetic, Epigenome, medicine.disease, 3. Good health, Leukemia, 030104 developmental biology, Oncology, Cancer research, business, Ex vivo, Research Paper
Abstract: Contains fulltext : 197351.pdf (Publisher’s version ) (Open Access) Epigenetic alterations have been associated with both pathogenesis and progression of cancer. By screening of library compounds, we identified a novel hybrid epi-drug MC2884, a HAT/EZH2 inhibitor, able to induce bona fide cancer-selective cell death in both solid and hematological cancers in vitro, ex vivo and in vivo xenograft models. Anticancer action was due to an epigenome modulation by H3K27me3, H3K27ac, H3K9/14ac decrease, and to caspase-dependent apoptosis induction. MC2884 triggered mitochondrial pathway apoptosis by up-regulation of cleaved-BID, and strong down-regulation of BCL2. Even aggressive models of cancer, such as p53(-/-) or TET2(-/-) cells, responded to MC2884, suggesting MC2884 therapeutic potential also for the therapy of TP53 or TET2-deficient human cancers. MC2884 induced massive apoptosis in ex vivo human primary leukemia blasts with poor prognosis in vivo, by targeting BCL2 expression. MC2884-treatment reduced acetylation of the BCL2 promoter at higher level than combined p300 and EZH2 inhibition. This suggests a key role for BCL-2 reduction in potentiating responsiveness, also in combination therapy with BCL2 inhibitors. Finally, we identified both the mechanism of MC2884 action as well as a potential therapeutic scheme of its use. Altogether, this provides proof of concept for the use of epi-drugs coupled with epigenome analyses to 'personalize' precision medicine.
Published: 2018
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24. Causes and Consequences of Microtubule Acetylation

Author: Guillaume Montagnac, Carsten Janke, Institut Curie [Paris], Stress génotoxiques et cancer, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Paris-Sud - Paris 11 (UP11), Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR), Hématopoïèse normale et pathologique (U1170 Inserm), and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Lysine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Microtubules, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Microtubule, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Cytoskeleton, 030102 biochemistry & molecular biology, biology, Structural integrity, Acetylation, Microtubule lumen, Biomechanical Phenomena, Cell biology, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, 030104 developmental biology, Tubulin, biology.protein, Tubulin acetylation, Stress, Mechanical, General Agricultural and Biological Sciences, Protein Processing, Post-Translational
Abstract: Among the different types of cytoskeletal components, microtubules arguably accumulate the greatest diversity of post-translational modifications (PTMs). Acetylation of lysine 40 (K40) of α-tubulin has received particular attention because it is the only tubulin PTM to be found in the lumen of microtubules: most other tubulin PTMs are found at the outer surface of the microtubule. As a consequence, the enzyme catalyzing K40 acetylation needs to penetrate the narrow microtubule lumen to find its substrate. Acetylated microtubules have been considered to be stable, long-lived microtubules; however, until recently, there was little information about whether the longevity of these microtubules is the cause or the consequence of acetylation. Current advances suggest that this PTM helps the microtubule lattice to cope with mechanical stress, thus facilitating microtubule self-repair. These observations now shed new light on the structural integrity of microtubules, as well as on the mechanisms and biological functions of tubulin acetylation. Here, we discuss recent insights into how acetylation is generated in the lumen of microtubules, and how this 'hidden' PTM can control the properties and functions of microtubules.
Published: 2017
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25. Critical role of the HDAC6–cortactin axis in human megakaryocyte maturation leading to a proplatelet-formation defect

Author: Jean-Pierre Marolleau, Delphine Muller, Dominika Sliwa, Khadija M. Diop, Steven G. Thomas, Gérard Pierron, Alberta Palazzo, Patrick Matthias, Nathalie Droin, Isabelle Godin, Isabelle Plo, Philippe Rameau, Hana Raslova, Sylvie Souquere, Stephen P. Watson, Kahia Messaoudi, Najet Debili, William Vainchenker, Olivier Bluteau, Rameez Ishaq, Ashfaq Ali, Valérie Lapierre, Hématopoïèse normale et pathologique (U1170 Inserm), and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Blood Platelets, 0301 basic medicine, Indoles, Science, General Physics and Astronomy, macromolecular substances, Histone Deacetylase 6, Hydroxamic Acids, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Megakaryocyte, medicine, Animals, Humans, Gene silencing, Cytoskeleton, lcsh:Science, Cells, Cultured, Actin, Mice, Knockout, Gene knockdown, Multidisciplinary, biology, Chemistry, Acetylation, Cell Differentiation, General Chemistry, HDAC6, Thrombocytopenia, 3. Good health, Cell biology, Histone Deacetylase Inhibitors, Pyrimidines, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030104 developmental biology, medicine.anatomical_structure, biology.protein, RNA Interference, lcsh:Q, Histone deacetylase, Cortactin, Megakaryocytes
Abstract: Thrombocytopenia is a major side effect of a new class of anticancer agents that target histone deacetylase (HDAC). Their mechanism is poorly understood. Here, we show that HDAC6 inhibition and genetic knockdown lead to a strong decrease in human proplatelet formation (PPF). Unexpectedly, HDAC6 inhibition-induced tubulin hyperacetylation has no effect on PPF. The PPF decrease induced by HDAC6 inhibition is related to cortactin (CTTN) hyperacetylation associated with actin disorganization inducing important changes in the distribution of megakaryocyte (MK) organelles. CTTN silencing in human MKs phenocopies HDAC6 inactivation and knockdown leads to a strong PPF defect. This is rescued by forced expression of a deacetylated CTTN mimetic. Unexpectedly, unlike human-derived MKs, HDAC6 and CTTN are shown to be dispensable for mouse PPF in vitro and platelet production in vivo. Our results highlight an unexpected function of HDAC6–CTTN axis as a positive regulator of human but not mouse MK maturation., Histone deacetylase (HDAC) inhibitors, a class of cancer therapeutics, cause thrombocytopenia via an unknown mechanism. Here, the authors show that HDAC6 inhibition impairs proplatelet formation in human megakaryocytes, and show that this is linked to hyperacetylation of the actin-binding protein cortactin.
Published: 2017
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26. AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

Author: Olivia Bawa, Monika Pilichowska, Paule Opolon, Jeffrey O. Saunders, Fang Wang, Cyril Quivoron, Anil K. Padyana, Zenon D. Konteatis, Kimberly Straley, Erica Tobin, Sophie Broutin, Marion Dorsch, Hua Yang, Byron DeLaBarre, Jeremy Travins, Sung Choe, Yue Chen, Lei Jin, Wentao Wei, Virginie Penard-Lacronique, Raj Nagaraja, Wei Liu, Lenny Dang, Shengfang Jin, Cheng Fang, Lee Silverman, Fan Jiang, Katharine E. Yen, Giovanni Cianchetta, Olivier Bernard, Erin Artin, Muriel D. David, Shin-San Michael Su, Stefan Gross, Francesco G. Salituro, Véronique Saada, Stéphane de Botton, Scott A. Biller, Angelo Paci, Benoit S. Marteyn, Yingxia Xu, Agios Pharmaceuticals, Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Plateforme d’évaluation préclinique (PFEP), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pharmacologie, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Laboratoire de thérapie cellulaire, Département de médecine oncologique [Gustave Roussy], Pathogénie microbienne moléculaire, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Tufts Medical Center, ShangPharma, Viva Biotech Ltd., and This work was funded by Agios Pharmaceuticals, Inc., the French National Institute of Health (INSERM-AVIESAN), the National Cancer Institute (INCa-DGOS-Inserm_6043 and INCa 2012-1-RT-09), and the Fondation Association pour la Recherche sur le Cancer (ARC, SL220130607089 Programme Labellisé to V. Penard-Lacronique and S. de Botton). M.D. David is funded by a fellowship from the Institut National du Cancer (INCa-DGOS_5733).
Subjects: 0301 basic medicine, Myeloid, IDH1, Cellular differentiation, Myeloid leukemia, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Enasidenib, medicine.disease, Molecular biology, IDH2, 03 medical and health sciences, Leukemia, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Isocitrate dehydrogenase, Oncology, 030220 oncology & carcinogenesis, medicine
Abstract: Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate–dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation–positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation–positive advanced hematologic malignancies. Significance: Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. Cancer Discov; 7(5); 478–93. ©2017 AACR. See related commentary by Thomas and Majeti, p. 459. See related article by Shih et al., p. 494. This article is highlighted in the In This Issue feature, p. 443
Published: 2017
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27. ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia

Author: Arnaud Petit, Françoise Pflumio, Cécile Thirant, Cécile K. Lopez, Sébastien Malinge, Hana Raslova, Aurelie Siret, Olivier A. Bernard, Clarisse Thiollier, Cathy Ignacimouttou, Mehdi Khaled, M'Boyba Diop, Jürg Schwaller, William Vainchenker, John D. Crispino, Paola Ballerini, Guy Leverger, Ce ' Line Lefebvre, Philippe Rameau, Benjamin T. Kile, Catherine Carmichael, Lou Le Mouel, Eric Soler, Phillipe Dessen, Thomas Mercher, Zakia Aid, Julie Riviere, Nathalie Droin, Christian Wichmann, Camille Lobry, Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme imagerie et cytométrie ( PFIC ), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse ( AMMICa ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Ondes et Imagerie ( O&I ), Laboratoire de Mécanique et d'Acoustique [Marseille] ( LMA ), Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ), Hôpital Trousseau, CHRU Tours, CHU Trousseau [APHP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ), Centre de génétique et de physiologie moléculaire et cellulaire ( CGPhiMC ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Northwestern University Chicago, Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ), Plateforme de génomique, Laboratoire des Adaptations Physiologiques aux Activités Physiques ( LAPHAP ), Université de Poitiers, Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon
Subjects: Transcriptional Activation, 0301 basic medicine, Cancer Research, Oncogene Proteins, Fusion, ChIP, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 03 medical and health sciences, Acute megakaryoblastic leukemia, Transcriptional Regulator ERG, GLIS2, Downregulation and upregulation, Leukemia, Megakaryoblastic, Acute, Transcription (biology), medicine, Animals, Humans, GATA1 Transcription Factor, Child, Enhancer, Gene, Transcription factor, transcription factor, CBFA2T3, AMKL, leukemia, Cell Differentiation, GLIS, medicine.disease, Leukemia, pediatric, Enhancer Elements, Genetic, 030104 developmental biology, Oncology, ERG, CRISPR, Cancer research, enhancer
Abstract: International audience; Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia.
Published: 2017
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28. AMPK activation alleviates stroke severity in mice with chronic kidney disease

Author: Grissi, M., Boudot, Cédric, Assem, Maryam, Poirot-Leclercq, S., Lando, M., Boullier, Agnès, Lenglet, G., Avondo, Carine, Candellier, Alexandre, Lalau, Jean-Daniel, Choukroun, Gabriel, Massy, Z. A., Kamel, Saïd, Chillon, Jean-Marc, Henaut, L., DESSAIVRE, Louise, Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Université de Picardie Jules Verne (UPJV), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génie Enzymatique et Cellulaire (GEC), Université de Technologie de Compiègne (UTC)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, CHU Amiens-Picardie, Épidémiologie et recherches translationnelles sur les maladies rénales et cardiovasculaires (EPREC) (U1018 (Équipe 5)), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Ambroise Paré [AP-HP], Département Intelligence Ambiante et Systèmes Interactifs (DIASI), Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract: e-Poster, World Stroke Congress Abstracts, 2020 -; International audience; Background and aims: Ischemic stroke is highly prevalent in patients with chronic kidney disease(CKD) and has been associated with poor outcomes. In experimental studies, CKD mice display widerand more inflammatory ischemic lesions as well as poorer functional outcomes than mice with normalrenal function. Our group recently showed that adenosine-monophosphate-activated protein kinase(AMPK) activation is impaired within ischemic lesions of CKD mice. In rodents with normal renalfunction, AMPK activation by metformin, an anti-diabetic drug, improved stroke outcomes. This workaimed to investigate whether a 5-week pre-conditioning with metformin can restore AMPK activity andimprove functional recovery in mice with CKD.Methods: . Eight-week old female C57BL/6J mice were assigned to CKD or SHAM groups. CKD wasinduced through right kidney cortical electrocautery followed by left total nephrectomy. Mice receivedmetformin (200 mg/kg/day) or vehicle in drinking water. The treatment began 1 week after CKDinduction and was given for 5 weeks until stroke induction by transient middle cerebral artery occlusion (tMCAO).Results: . Exposure to metformin rescued AMPK activation, decreased ischemic lesion size andimproved neurological score, grip strength and prehensile abilities in CKD mice. Ischemic hemisphereof CKD mice exposed to metformin displayed decreased microglia/macrophages pro-inflammatory M1signature genes’ expression (i.e. CD32, CD16, CD86, IL-1b and iNOS) as well as reduced activation ofthe canonical NF-KB pathway.Conclusions: . These data demonstrate that the AMPK could be a promising therapeutic target todecrease brain inflammation and improve stroke recovery in CKD
Published: 2020
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29. SUGT1 controls susceptibility to HIV-1 infection by stabilizing microtubule plus-ends

Author: Guido Kroemer, Audrey Paoletti, Awatef Allouch, Gabrielle Lê-Bury, Marie-Lise Gougeon, Cristina Di Primio, Annie David, Mauro Piacentini, Gianfranco Pancino, Guillaume Montagnac, Valentina Quercioli, Jean-Luc Perfettini, Asier Sáez-Cirión, Anna Cereseto, Roberta Nardacci, Frédéric Subra, David M. Ojcius, Florence Niedergang, Héla Saïdi, Saez-Cirion, Asier, Instituts Hospitalo-Universitaires B - Institut de Médecine Personnalisée du Cancer - - MMO (IHU-CANCER)2010 - ANR-10-IBHU-0001 - IBHU - VALID, Institut Gustave Roussy (IGR), Radiothérapie Moléculaire et Innovation Thérapeutique (RaMo-IT), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université Paris-Saclay, Scuola Normale Superiore di Pisa (SNS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de biologie et pharmacologie appliquée (LBPA), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), National Institute for Infectious Diseases 'Lazzaro Spallanzani', HIV, Inflammation et persistance - HIV, Inflammation and Persistence, Institut Pasteur [Paris] (IP), Immunité Antivirale, Biothérapie et Vaccins, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), University of Trento [Trento], Arthur A. Dugoni School of Dentistry [San Francisco], University of the Pacific [San Francisco], University of the Pacific-University of the Pacific, Université Paris Diderot - Paris 7 (UPD7), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Istituto Nazionale di Malattie Infettive 'Lazzaro Spallanzani' (INMI), Università degli Studi di Roma Tor Vergata [Roma], Université Paris Descartes - Paris 5 (UPD5), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Métabolisme, cancer et immunité = Metabolism, Cancer & Immunity [CRC] (Equipe labellisée Ligue contre le cancer), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Department of Women's and Children's Health, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], This work was supported by funds from Agence Nationale de la Recherche (ANR-10-IBHU-0001, ANR-10-LABX33, and ANR-11-IDEX-003-01), Cancéropole Ile de France, Electricité de France, Fondation Gustave Roussy, Institut National du Cancer (INCA 9414), NATIXIS, SIDACTION, and the French National Agency for Research on AIDS and viral Hepatitis (ANRSH) (to J-LP and FN)., We acknowledge Dr Alessandro Donado, Yann Lecluse, Floriane Herit, and Pierre Bourdoncle (IMAG’IC facility of Institut Cochin) for their technical support, and Pr. Eric Solary for the pRLL-EF1-PGK-GFP lentiviral vector plasmid., ANR-10-IBHU-0001,MMO (IHU-CANCER),Institut de Médecine Personnalisée du Cancer(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), HIV, Inflammation et persistance, Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE)
Subjects: 0301 basic medicine, Permissiveness, Cell, Mutant, Drug Resistance, Cell Cycle Proteins, HIV Infections, Virus Replication, Microtubules, Medical and Health Sciences, 0302 clinical medicine, 2.2 Factors relating to the physical environment, 2.1 Biological and endogenous factors, Viral, Aetiology, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Acetylation, Biological Sciences, Active Transport, 3. Good health, medicine.anatomical_structure, Infectious Diseases, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, HIV/AIDS, Infectious diseases, Infection, Microtubule-Associated Proteins, medicine.drug, Biochemistry & Molecular Biology, Immunopathogenesis, Anti-HIV Agents, Active Transport, Cell Nucleus, Biology, Article, Virus, microtubules, 03 medical and health sciences, Microtubule, Raltegravir Potassium, Drug Resistance, Viral, medicine, Genetics, Humans, Permissive, Molecular Biology, Cell Nucleus, Cell Biology, Raltegravir, Virology, nuclear import, 030104 developmental biology, HIV-1, SUGT1
Abstract: International audience; Understanding the viral-host cell interface during HIV-1 infection is a prerequisite for the development of innovative antiviral therapies. Here we show that the suppressor of G2 allele of skp1 (SUGT1) is a permissive factor for human immunodeficiency virus (HIV)-1 infection. Expression of SUGT1 increases in infected cells on human brain sections and in permissive host cells. We found that SUGT1 determines the permissiveness to infection of lymphocytes and macrophages by modulating the nuclear import of the viral genome. More importantly, SUGT1 stabilizes the microtubule plus-ends (+MTs) of host cells (through the modulation of microtubule acetylation and the formation of end-binding protein 1 (EB1) comets). This effect on microtubules favors HIV-1 retrograde trafficking and replication. SUGT1 depletion impairs the replication of HIV-1 patient primary isolates and mutant virus that is resistant to raltegravir antiretroviral agent. Altogether our results identify SUGT1 as a cellular factor involved in the post-entry steps of HIV-1 infection that may be targeted for new therapeutic approaches.
Published: 2020
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30. Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

Author: Veronique, Della-Valle, Damien, Roos-Weil, Laurianne, Scourzic, Enguerran, Mouly, Zakia, Aid, Walaa, Darwiche, Yann, Lecluse, Frederik, Damm, Sylvie, Mémet, Thomas, Mercher, Said, Aoufouchi, Florence, Nguyen-Khac, Olivier A, Bernard, Hussein, Ghamlouch, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, Plateforme imagerie et cytométrie (PFIC), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Humboldt University Of Berlin, Berlin Institute of Health (BIH), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Intégrité du génome et cancers (IGC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humboldt-Universität zu Berlin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], and Gestionnaire, Hal Sorbonne Université
Subjects: Chronic lymphocytic leukaemia, B cells, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, B-cell lymphoma, [SDV]Life Sciences [q-bio], Oncogenes, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Leukemia, Lymphocytic, Chronic, B-Cell, lcsh:RC254-282, Article, [SDV] Life Sciences [q-bio], Mice, Proto-Oncogene Proteins, Animals, I-kappa B Proteins, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Aberrant NF-κB activation is a hallmark of most B-cell malignancies. Recurrent inactivating somatic mutations in the NFKBIE gene, which encodes IκBε, an inhibitor of NF-κB-inducible activity, are reported in several B-cell malignancies with highest frequencies in chronic lymphocytic leukemia and primary mediastinal B-cell lymphoma, and account for a fraction of NF-κB pathway activation. The impact of NFKBIE deficiency on B-cell development and function remains, however, largely unknown. Here, we show that Nfkbie-deficient mice exhibit an amplification of marginal zone B cells and an expansion of B1 B-cell subsets. In germinal center (GC)-dependent immune response, Nfkbie deficiency triggers expansion of GC B-cells through increasing cell proliferation in a B-cell autonomous manner. We also show that Nfkbie deficiency results in hyperproliferation of a B1 B-cell subset and leads to increased NF-κB activation in these cells upon Toll-like receptor stimulation. Nfkbie deficiency cooperates with mutant MYD88 signaling and enhances B-cell proliferation in vitro. In aged mice, Nfkbie absence drives the development of an oligoclonal indolent B-cell lymphoproliferative disorders, resembling monoclonal B-cell lymphocytosis. Collectively, these findings shed light on an essential role of IκBε in finely tuning B-cell development and function.
Published: 2020
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31. XPO1 regulates erythroid differentiation and is a new target for the treatment of β-thalassemia

Author: Guillem, Flavia, Dussiot, Michael, Colin, Elia, Suriyun, Thunwarat, Arlet, Jean Benoit, Goudin, Nicolas, Marcion, Guillaume, Seigneuric, Renaud, Causse, Sebastien, Gonin, Patrick, Gastou, Marc, Deloger, Marc, Rossignol, Julien, Lamarque, Mathilde, Bellaid Choucair, Zakia, Gautier, Emilie Fleur, Ducamp, Sarah, Vandekerckhove, Julie, Moura, Ivan, Maciel, Thiago, Garrido, Carmen, An, Xiuli, Mayeux, Patrick, Mohandas, Narla, COURTOIS, genevieve, Hermine, Olivier, Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme d'Imagerie Cellulaire [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Institut Gustave Roussy (IGR), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Eléments transposables, évolution, populations, Département génétique, interactions et évolution des génomes [LBBE] (GINSENG), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Red Cell Physiology Laboratory [New York, USA], New York Blood Center, Service d'hématolgie adulte, Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut des Maladies Génétiques Imagine [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), COURTOIS, genevieve, and UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC)
Subjects: [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, hemic and lymphatic diseases, Article, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: β-thalassemia major (β-TM) is an inherited hemoglobinopathy caused by a quantitative defect in the synthesis of β-globin chains of hemoglobin, leading to the accumulation of free a-globin chains that aggregate and cause ineffective erythropoiesis. We have previously demonstrated that terminal erythroid maturation requires a transient activation of caspase-3 and that the chaperone Heat Shock Protein 70 (HSP70) accumulates in the nucleus to protect GATA-1 transcription factor from caspase-3 cleavage. This nuclear accumulation of HSP70 is inhibited in human β-TM erythroblasts due to HSP70 sequestration in the cytoplasm by free a-globin chains, resulting in maturation arrest and apoptosis. Likewise, terminal maturation can be restored by transduction of a nuclear-targeted HSP70 mutant. Here we demonstrate that in normal erythroid progenitors, HSP70 localization is regulated by the exportin-1 (XPO1), and that treatment of β-thalassemic erythroblasts with an XPO1 inhibitor increased the amount of nuclear HSP70, rescued GATA-1 expression and improved terminal differentiation, thus representing a new therapeutic option to ameliorate ineffective erythropoiesis of β-TM.
Published: 2019
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32. Toll-like receptor 2 expression on c-kit+ cells tracks the emergence of embryonic definitive hematopoietic progenitors

Author: Dominik Filipp, Vladimír Kořínek, Jana Balounova, Andrea Jurisicova, Isabelle Godin, Jan Prochazka, Radislav Sedlacek, Martina Dobešová, Meritxell Alberich-Jorda, Karel Fiser, Iva Splichalova, Hoon Ki Sung, Michal Kolář, Hématopoïèse normale et pathologique (U1170 Inserm), and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Male, Science, General Physics and Astronomy, Locus (genetics), Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Fate mapping, Animals, Progenitor cell, 10. No inequality, lcsh:Science, Toll-like receptor, Multidisciplinary, General Chemistry, Hematopoietic Stem Cells, Embryonic stem cell, Phenotype, Toll-Like Receptor 2, Cell biology, Hematopoiesis, Mice, Inbred C57BL, Haematopoiesis, Adult Stem Cells, Proto-Oncogene Proteins c-kit, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030104 developmental biology, 030220 oncology & carcinogenesis, lcsh:Q, Female, Stem cell
Abstract: Hematopoiesis in mammalian embryos proceeds through three successive waves of hematopoietic progenitors. Since their emergence spatially and temporally overlap and phenotypic markers are often shared, the specifics regarding their origin, development, lineage restriction and mutual relationships have not been fully determined. The identification of wave-specific markers would aid to resolve these uncertainties. Here, we show that toll-like receptors (TLRs) are expressed during early mouse embryogenesis. We provide phenotypic and functional evidence that the expression of TLR2 on E7.5 c-kit+ cells marks the emergence of precursors of erythro-myeloid progenitors (EMPs) and provides resolution for separate tracking of EMPs from primitive progenitors. Using in vivo fate mapping, we show that at E8.5 the Tlr2 locus is already active in emerging EMPs and in progenitors of adult hematopoietic stem cells (HSC). Together, this data demonstrates that the activation of the Tlr2 locus tracks the earliest events in the process of EMP and HSC specification., There is limited knowledge of markers to identify various waves of murine embryonic hematopoiesis. Here, the authors show that the expression of toll-like receptor 2 (TLR2) on E7.5 c-kit+ cells marks the emergence of erythro-myeloid progenitor precursors and that the Tlr2 locus is active in E8.5 precursors of adult HSCs.
Published: 2019
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33. L’hématopoïèse clonale : un concept émergent à la croisée des spécialités

Author: J.-B. Micol, M. Papo, F.-X. Danlos, Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and CCSD, Accord Elsevier
Subjects: 0301 basic medicine, Myeloid, Somatic cell, Basic science, [SDV]Life Sciences [q-bio], Gastroenterology, Myeloid leukemia, Biology, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, Haematopoiesis, 030104 developmental biology, 0302 clinical medicine, Increased risk, medicine.anatomical_structure, Hematologic disease, 030220 oncology & carcinogenesis, Immunology, Internal Medicine, medicine, Gene, ComputingMilieux_MISCELLANEOUS
Abstract: Clonal hematopoiesis of undetermined significance or CHIP describes the identification, in individuals without hematologic disease, of one or more somatic mutations in hematopoietic cells. These mutations, detected by high-throughput genes sequencing (Next-Generation Sequencing or NGS), affect genes first identified in acute myeloid leukemia or myelodysplastic syndrome, such as DNMT3A, TET2 and ASXL1. CHIP is associated with an increased risk of malignant hemopathy, both myeloid and lymphoid, evaluated from 0.5 to 1% per year. CHIP is also associated with an increased risk of overall mortality and cardiovascular diseases. CHIP detection using NGS is currently limited to basic science field, but recent studies suggest that it may be of clinical interest.
Published: 2019
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34. Role du confinement sur l'endocytose dépendante de la clathrine

Author: Le devedec, Dahiana, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Saclay (COmUE), and Guillaume Montagnac
Subjects: Récepteur à l'EGF, Frustrated endocytosis, Hb-Egf, Egfr, Clathrine, Endocytose frustrée, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Clathrin, Confinement
Abstract: Clathrin-mediated endocytosis (CME) is the major route of endocytosis for many cargos in eukaryotic cells. Endocytosis takes place at clathrin-coated pits (CCPs), small assemblies of clathrin and clathrin adaptors randomly distributed at the plasma membrane. Clathrin polymerization induces the progressive bending of the plasma membrane resulting in the formation of a vesicle budding off into the cytosol. CME is a highly dynamic process with an average lifetime of CCPs in the order of 30 seconds. In this manner, CME fulfills a range of different functions and enables cells to regulate the surface expression of proteins, to sample the cell’s environment for growth and guidance cues, to control the activation of signaling pathways and to turn over membrane components by sending these components for degradation in the endo-lysosomal pathway. A deregulation of the endocytic pathways was previously shown to be involve in cancer. These modifications can affect CME directly by modifying its actors, or indirectly with mutations on receptors or cargoes undertaken by CME. Tumor progression is dependent of several factors, the first one involving the accumulation of mutations which results in modifications in the cells themselves or on their surrounding environment by changing its biochemical and physical properties, leading to the formation of the tumor niche. These changes reciprocally foster cancer progression. During tumor growth, fibroblasts will be recruited around tumor cells, leading to the remodeling of the microenvironment and to an increase of rigidity nearby the tumor. This stiffness is sensed by the cells and send signals for proliferation and migration as a result. Stiffness sensing engages mainly integrins at the cell surface which will aggregate and initiate signaling cascades accountable for these responses. Integrins are capable of clustering into two types of structures: focal adhesions and clathrin-coated structures (CCSs). Regarding CCSs, it was shown previously that high stiffness strengthen the interaction between integrins and the substrate, hence preventing the budding off of the vesicle, and this is referred to as “frustrated endocytosis”. This holding of CCSs at the cell surface promotes a sustained signaling at the plasma membrane instead of a signal termination after internalization and further degradation in lysosomes. My PhD project relied on these previous findings, with a particular focus on another mechanical alteration observed in tumors, the confinement. Indeed, during the uncontrolled proliferation of cancer cells in a spatially restricted area, cells become subjected to compressive forces. The results I obtained indicate that confinement leads to frustrated endocytosis and hence to sustained signaling from the plasma membrane. In addition, compression also leads to HB-EGF shedding at the cell surface, and the resulting EGF product activate the EGFR in a paracrine manner, thus leading to the activation of the MAP kinase Erk signaling pathway. Indeed, both the absence of EGFR ligands in the medium and the inhibition of the shedding demonstrate the necessity of this mechanism in EGFR activation. To sum up, confinement induces the shedding of the EGFR pro-ligand HB-EGF necessary to EGFR activation in these conditions. Simultaneously, endocytosis is delayed and frustrated endocytosis leads to sustained signaling at the cell surface. Together, these events cooperate to strongly activate the Erk pathway. These findings highlight the interplay between the physical feature of the tumor environment and signaling pathways known to govern tumor growth.; L’endocytose dépendante de la clathrine (EDC) est la principale voie d’internalisation des récepteurs de surface et de leurs ligands. L’internalisation se fait suite à l’invagination de la membrane plasmique vers l’intérieur de la cellule suite à la formation, dans un premier temps, de puits recouverts de clathrine (PRCs) qui bourgeonnent ensuite en vésicules recouvertes de clathrine dans le cytosol. L’EDC est un processus très dynamique qui a lieu en l’espace de 30 sec-1mn. Elle est impliquée dans de multiples fonctions et permet ainsi à la cellule de réguler l’expression de ses protéines en surface, de répondre aux signaux de prolifération ou migration envoyés par l’environnement immédiat via l’activation de voies de signalisation spécifiques ou encore de réguler le renouvellement des composants de la membrane plasmique. De par son importance, des dérégulations de l’endocytose dépendante de la clathrine ont déjà été observées dans les cancers. Ces modifications peuvent impliquer directement l’EDC en modifiant ses composants ou indirectement lors d’altérations de récepteurs régulés par celle-ci. La progression tumorale est elle-même régulée par de multiples facteurs, notamment l’accumulation de mutations qui ont des conséquences sur les cellules cancéreuses elle-même ou bien sur l’environnement immédiat, formant ainsi la « niche tumorale ». Ces changements agissent réciproquement sur la progression tumorale afin de l’amplifier. Lors de la croissance tumorale, les cellules cancéreuses recrutent des fibroblastes qui vont participer au remodelage et à l’augmentation de la rigidité autour de la tumeur. La rigidité de la matrice extracellulaire est détectée par les cellules ce qui envoie des signaux déclencheurs de prolifération et de migration en conséquence. Cette détection passe essentiellement par les intégrines à la surface membranaire qui vont s’agréger et induire des cascades de signalisation impliquées dans ces réponses. Ces intégrines peuvent se regrouper dans deux types de structures, les adhésions focales et les structures recouvertes de clathrine. En ce qui concerne ces dernières, il a été démontré précédemment que la rigidité du substrat augmente sa force d’interaction avec les intégrines, et empêche ainsi l’internalisation des vésicules recouvertes de clathrine, on parle alors d’ « endocytose frustrée ». Cette rétention des structures recouvertes de clathrine à la surface provoque une signalisation soutenue à la surface au lieu de l’arrêter par dégradation ultérieure des récepteurs dans les lysosomes. Le laboratoire a démontré que les structures de clathrine frustrées capturent ainsi différent récepteurs conduisant à une signalisation accrue dans la voie de la MAP Kinase Erk. Mon projet de thèse repose sur ces observations en s’intéressant plus particulièrement au rôle d’une autre modification induite par la croissance tumorale, le confinement. En effet, en se multipliant de manière incontrôlée dans un environnement spatialement restreint, les cellules tumorales se retrouvent soumises à des forces de compression. Les résultats mis en évidence au cours de ma thèse ont montré que le confinement provoque, comme la rigidité, une frustration des structures de clathrine qui ne sont donc plus capables de soutenir l’endocytose des récepteurs. De plus, la compression cellulaire induit le clivage d’un pro-ligand de l’EGFR, le HB-EGF, ce qui conduit à l’activation paracrine de l’EGFR et à l’activation de la voie Erk. En effet, l’absence de facteurs de croissance dans le milieu ainsi que l’inhibition de ce clivage démontrent la nécessité de la mise en place de ce mécanisme. En résumé, le confinement induit le clivage du pro-ligand HB-EGF, qui à son tour va activer le récepteur à l’EGF. En parallèle, l’endocytose est ralentie et provoque une signalisation accrue à la membrane. Ces deux évènements coopèrent pour mener à une très forte activation de la voie Erk.
Published: 2019

35. Genetic characterization of B-cell prolymphocytic leukemia: a prognostic model involving MYC and TP53

Author: Olivier A. Bernard, Elodie Pramil, Florence Nguyen-Khac, Clementine Gabillaud, Nathalie Nadal, Elise Chapiro, Simon Bouzy, Frederic Davi, Stéphanie Struski, Damien Roos-Weil, Christine Lefebvre, Evelyne Callet-Bauchu, Magali Le Garff-Tavernier, Philippe Dessen, Virginie Eclache, Caroline Algrin, Jean-François Lesesve, Veronique Leblond, Lena Wagner, Claude Lesty, Sandra Fert-Ferrer, Melanie Yon, Ludovic Jondreville, Nathalie Auger, Jean Gabarre, Antoine Ittel, Marie-Agnès Collonge-Rame, Karim Maloum, Clémentine Dillard, M'Boyba Diop, Catherine Settegrana, Thorsten Zenz, Sebastian Scheinost, Baptiste Gaillard, Benoit Quilichini, Isabelle Radford-Weiss, Marc Muller, Nathalie Droin, Lucile Baseggio, Santos A. Susin, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Institut Gustave Roussy (IGR), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Hôpital Robert Debré, Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Strasbourg, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Métropole Savoie [Chambéry], CHU Necker - Enfants Malades [AP-HP], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Universität Zürich [Zürich] = University of Zurich (UZH), Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Hospitalier Mutualiste [Grenoble] (GHM), Hôpital Avicenne [AP-HP], Service d'hématologie [Reims], Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Génétique [CHRU Nancy], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Eurofins Biomnis, Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], and University hospital of Zurich [Zurich]
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Immunology, Chromosomal translocation, Biology, Biochemistry, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, 0302 clinical medicine, SETD2, B-cell prolymphocytic leukemia, medicine, Humans, Prolymphocytic leukemia, Aged, Aged, 80 and over, Chromosome Aberrations, Leukemia, Prolymphocytic, B-Cell, Cytogenetics, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, Middle Aged, medicine.disease, Prognosis, 3. Good health, Leukemia, 030104 developmental biology, Cytogenetic Analysis, Chromosome abnormality, Cancer research, Female, Tumor Suppressor Protein p53, IGHV@, 030215 immunology
Abstract: International audience; B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessment of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex ({greater than or equal to}3 abnormalities) in 73% of the patients and highly complex (>5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC [t(MYC)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six of the 34 patients (76%) exhibit MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1 The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%), and displayed significantly mutated IGHV genes (79%). We identified three distinct cytogenetic risk groups: low-risk (no MYC aberration), intermediate-risk (MYC aberration but no del17p), and high-risk (MYC aberration and del17p) (p=.0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif (BET) inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We conclude that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease.
Published: 2019
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36. Nuclear interacting SET domain protein 1 inactivation impairs GATA1-regulated erythroid differentiation and causes erythroleukemia

Author: Marwa Almosailleakh, Antoine H.F.M. Peters, Alexandar Tzankov, Thomas Bock, Sabine Juge, Matheus Filgueira Bezerra, Hélène Méreau, Frederik Otzen Bagger, Juerg Schwaller, Katharina Leonards, Samantha Tauchmann, Régine Losson, Thomas Mercher, Cécile Thirant, Robert Ivanek, University of Basel (Unibas), Swiss Institute of Bioinfomatics [Bâle, Suisse], University of Copenhagen = Københavns Universitet (KU), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Fiocruz Pernambuco - Instituto Aggeu Magalhães [Recife, Brésil], Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Ministério da Saúde [Brasília, Brazil], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Friedrich Miescher Institute for Biomedical Research (FMI), Novartis Research Foundation, This work was supported by funding from the Swiss Cancer League (SKL): KFS-3487-08-2014 and KFS-4258-08-2017, the Swiss National Science Foundation (SNF, 31003_A_173224/1), the Gertrude Von Meissner Foundation Basel, the Novartis Biomedical Research Foundation, Basel, the San Salvatore Foundation, Lugano (201525), and the Wilhelm-Sander Foundation, München (2017-035.1)., University of Copenhagen = Københavns Universitet (UCPH), and Bodescot, Myriam
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0301 basic medicine, Male, Erythroblasts, Cellular differentiation, Regulator, General Physics and Astronomy, Antigens, CD34, Kaplan-Meier Estimate, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Mice, 0302 clinical medicine, hemic and lymphatic diseases, GATA1 Transcription Factor, lcsh:Science, Regulation of gene expression, Gene knockdown, Multidisciplinary, Molecular medicine, Chemistry, Gene Expression Regulation, Leukemic, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, GATA1, Cell Differentiation, Chromatin, 3. Good health, Cell biology, DNA-Binding Proteins, Haematopoiesis, Proto-Oncogene Proteins c-kit, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, Erythropoiesis, Protein Binding, Adult, Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Biochemistry, Genetics and Molecular Biology, Article, Acute myeloid leukaemia, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Erythroid Cells, Antigens, CD, Cell Line, Tumor, Proto-Oncogene Proteins, Receptors, Transferrin, Animals, Humans, Cell Lineage, RNA, Messenger, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Histone-Lysine N-Methyltransferase, Hematopoiesis, 030104 developmental biology, Nuclear receptor, lcsh:Q, Leukemia, Erythroblastic, Acute
Abstract: The nuclear receptor binding SET domain protein 1 (NSD1) is recurrently mutated in human cancers including acute leukemia. We show that NSD1 knockdown alters erythroid clonogenic growth of human CD34+ hematopoietic cells. Ablation of Nsd1 in the hematopoietic system of mice induces a transplantable erythroleukemia. In vitro differentiation of Nsd1−/− erythroblasts is majorly impaired despite abundant expression of GATA1, the transcriptional master regulator of erythropoiesis, and associated with an impaired activation of GATA1-induced targets. Retroviral expression of wildtype NSD1, but not a catalytically-inactive NSD1N1918Q SET-domain mutant induces terminal maturation of Nsd1−/− erythroblasts. Despite similar GATA1 protein levels, exogenous NSD1 but not NSDN1918Q significantly increases the occupancy of GATA1 at target genes and their expression. Notably, exogenous NSD1 reduces the association of GATA1 with the co-repressor SKI, and knockdown of SKI induces differentiation of Nsd1−/− erythroblasts. Collectively, we identify the NSD1 methyltransferase as a regulator of GATA1-controlled erythroid differentiation and leukemogenesis., Loss of function mutations of NSD1 occur in blood cancers. Here, the authors report that NSD1 loss blocks erythroid differentiation which leads to an erythroleukemia-like disease in mice by impairing GATA1-induced target gene activation.
Published: 2019
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37. Functions of the transcription factor Lyl-1 in the hematopoietic development of the embryo : Focus on yolk sac macrophages and hematopoietic stem cells

Author: Ren, Deshan, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Saclay (COmUE), Isabelle Godin, and STAR, ABES
Subjects: Macrophage, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Sac vitellin, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Development, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cellules souches hématopoïétiques, Lyl-1, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Hematopoietic stem cells, Yolk sac, Développement
Abstract: During ontogeny, hematopoietic progenitors are generated in three independent waves, the first two (primitive and transient definitive) develop from the yolk sac (YS), before the appearance of Hematopoietic Stem Cells (HSC) that occurs later in the Aorta‐Gonad‐Mesonephros (AGM), in the third and definitive wave. Both Tal1/SCL and its paralog Lyl‐1 belong to the transcriptional complex that regulates hematopoietic progenitor development. While Tal‐1/SCL is mandatory for the specification of hematopoietic progenitors from the three embryonic waves, to date the functions of Lyl‐1 during developmental hematopoiesis remains largely unknown. By making use of the lacZ reporter from the Lyl‐1lacZ mice, we previously found that Lyl‐1 marks and regulates YS macrophage progenitors from the primitive wave (MΦPrim), and embryonic microglia. In a RNA‐seq analysis, we show that MΦPrim gene expression landscape is clearly distinct from later transient definitive MΦ progenitors, reflecting their primitive status. Lyl‐1 invalidation also influences some inflammatory signalling pathways and also leads to the abnormal activation of microglia genes involved in synaptic regulation. In the definitive wave, we found that Lyl‐1 disruption leads to a reduced efficiency of long‐term reconstitution by HSC from embryonic day (E)10 AGM and reduced HSC pool size in E12 and E14 fetal liver. The reduction of the HSC pool results from a higher apoptosis level in Lyl‐1LacZ/LacZ HSCs restricted to the AGM stage. Together, our data establish that Lyl‐1 regulates the development of MΦPrim progenitors and HSC pool size soon after they are generated., Pendant l'ontogenèse, les progéniteurs hématopoïétiques sont générés en 3 vagues indépendantes. Les 2 premières (primitive, puis transitoire définitive) ont lieu dans le sac vitellin (SV), avant la génération des Cellules Souches Hématopoïétiques (CSH), qui apparaissent plus tard au niveau de la région "Aorta‐Gonad‐Mesonephros" (AGM), lors de la 3ème vague, dite définitive. Tal1/SCL et son paralogue Lyl‐1 appartiennent à un complexe transcriptionnel qui régule le développement hématopoïétique. Tal‐1/SCL est indispensable à la spécification des progéniteurs hématopoïétiques des 3 vagues. Par contre, le rôle de Lyl‐1 lors du développement hématopoïétique est mal connu. Grâce au gène rapporteur lacZ des souris Lyl‐1lacZ, nous montrons que Lyl‐1 marque et régule les progéniteurs macrophagiques primitifs (MΦPrim) du SV, ainsi que la microglie. Notre analyse en RNA‐seq montre que l'ensemble des gènes exprimés par les progéniteurs MΦPrim est bien distinct de celui des progéniteurs MΦ transitoire définitifs, plus tardifs, reflétant le statut primitif des MΦPrim. De plus, l'invalidation de Lyl‐1 influence les voies de signalisations de l'inflammation et conduit à une activation anormale des gènes de la microglie impliqués dans la régulation synaptique. Lors de la 3ème vague du développement hématopoïétique, nous montrons que l'invalidation de Lyl‐1 conduit à une diminution de l'activité des reconstitutions à long terme des CSH de l'AGM à E10 et à une réduction de la population de CSH dans le foie fœtal à E12 et E14. La réduction de la population de CSH semble liée uniquement à un taux accru d'apoptose des CSH Lyl‐1LacZ/LacZ uniquement au stade de l'AGM. En conclusion, nos résultats montrent que Lyl‐1 régule la production des progéniteurs MΦ primitifs, le développement de la microglie et celui des CSH, dont il contrôle la taille de la population, peu après leur génération.
Published: 2019

38. Familial predisposition to TP53/complex karyotype MDS and leukemia in DNA repair-deficient xeroderma pigmentosum

Author: Nathalie Droin, Alain Sarasin, Jean-Luc Schmutz, Stéphane de Botton, Samuel Quentin, Anna Raimbault, Filippo Rosselli, Alain Taieb, Véronique Saada, Vahid Asnafi, Jean Soulier, Yannick Boursin, Philippe Dessen, Patricia Kannouche, Thierry Leblanc, Nathalie Auger, Caroline Robert, Flore Sicre de Fontbrune, Mourad Sahbatou, Laurianne Drieu La Rochelle, Marie Sebert, Carlos Frederico Martins Menck, Eric Solary, Génomes et cancer (GC (FRE2939)), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB), Fondation Jean Dausset CEPH, Laboratory of Hematology, Gustave Roussy, Villejuif, Praxiling (Praxiling), Centre National de la Recherche Scientifique (CNRS)-Université Paul-Valéry - Montpellier 3 (UPVM), Plateforme de Bioinformatique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Service de Dermatologie et Allergologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Universidade de Sao Paulo, Institute of Biomedical Sciences, Universidade de São Paulo (USP)-Institute of Biomedical Sciences (ICB/USP), Universidade de São Paulo (USP), Stabilité Génétique et Oncogenèse (UMR 8200), Hematopoïèse et Cellules Souches (U362), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service d'hématologie et immunologie pédiatrique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Gustave Roussy (IGR), Radiothérapie moléculaire (UMR 1030), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), 3UMR728 INSERM Unité d'immuno-hématologie (UIH) and laboratoire d'hématologie, Hôpital St-Louis, AP-HP, Centre National de la Recherche Scientifique (CNRS), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Praxiling UMR 5267 (Praxiling), Université Paul-Valéry - Montpellier 3 (UM3)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: 0301 basic medicine, Xeroderma pigmentosum, DNA repair, [SDV]Life Sciences [q-bio], Immunology, medicine.disease_cause, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Complex Karyotype, Familial predisposition, medicine, Letter to Blood, Gene, ComputingMilieux_MISCELLANEOUS, Genetics, Mutation, business.industry, Cell Biology, Hematology, medicine.disease, 3. Good health, Leukemia, 030104 developmental biology, 030220 oncology & carcinogenesis, business, Founder effect
Abstract: There is a Blood Commentary on this article in this issue.
Published: 2019
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39. Murine platelet production is suppressed by S1P release in the hematopoietic niche, not facilitated by blood S1P sensing

Author: Najet Debili, Benoit Decouture, Sylvain Provot, Mari Kono, Eric Camerer, Ludovic Couty, Richard L. Proia, Maria L. Allende, Boubacar Mariko, Erica De Candia, Sonia Poirault-Chassac, Hira Niazi, Pierre-Louis Tharaux, Pierre Hadrien Becker, Véronique Baudrie, Christilla Bachelot-Loza, Rameez Ishaq, Nesrine Zoghdani, Anja Nitzsche, Alexandre Leuci, Yetki Aslan, Salome L. Gazit, Jerold Chun, Ammar Benarab, Patrice Therond, Pascale Gaussem, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Institute of Diabetes and Digestive and Kidney Diseases [Bethesda], University of Segou, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Hôpital Lariboisière, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Bicêtre, Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Laboratoire d'Etudes des Techniques et Instruments d'Analyse Moleculaire (LETIAM), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11), Università cattolica del Sacro Cuore [Roma] (Unicatt), Sanford Burnham Prebys Medical Discovery Institute, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), The Leducq Foundation (SphingoNet) (R.L.P. and E.C.), Fondation de France (E.C.), Higher Education Commission, Pakistan (H.N. and R.I.), ANR-10-MIDI-0003,GROVI,La règlulation de l'intégrité vasculaire par les GPCRs(2010), Camerer, Eric, and MECANISMES INTEGRES DE L'INFLAMMATION - La règlulation de l'intégrité vasculaire par les GPCRs - - GROVI2010 - ANR-10-MIDI-0003 - MI2 - VALID
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Blood Platelets, 0301 basic medicine, [SDV]Life Sciences [q-bio], Thrombopoiesis, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Sphingosine, megakaryocytes, Settore MED/04 - PATOLOGIA GENERALE, Animals, Platelet, Stem Cell Niche, Sphingosine-1-Phosphate Receptors, S1PR1, S1PR2, Megakaryopoiesis, Mice, Knockout, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, sphingolipids, Chemistry, organic chemicals, Sphingosine Kinase 2, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Platelets and Thrombopoiesis, Platelet production, Cell biology, [SDV] Life Sciences [q-bio], SPHK2, 030104 developmental biology, S1P receptors, lipids (amino acids, peptides, and proteins), Lysophospholipids, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract: International audience; Key points • The vascular S1Pgradient is dispensablefor platelet formationin mice• Instead, local S1P production restrains megakaryopoiesis via S1P 1 and can further suppress platelet production via S1P 2 when deregulated. AbstractThe bioactive lipid mediator sphingosine 1-phosphate (S1P) was recently assigned critical roles in platelet biology: whereas S1P 1 receptor-mediated S1P gradient sensing was reported to be essential for directing proplatelet extensions from megakaryocytes (MKs) toward bone marrow sinusoids, MK sphingosine kinase 2 (Sphk2)-derived S1P was reported to further promote platelet shedding through receptor-independent intracellular actions, and platelet aggregation through S1P 1. Yet clinical use of S1P pathway modulators including fingolimod has not been associated with risk of bleeding or thrombosis. We therefore revisited the role of S1P in platelet biology in mice. Surprisingly, no reduction in platelet counts was observed when the vascular S1P gradient was ablated by impairing S1P provision to plasma or S1P degradation in interstitial fluids, nor when gradient sensing was impaired by S1pr1 deletion selectively in MKs. Moreover, S1P 1 expression and signaling were both undetectable in mature MKs in situ, and MK S1pr1 deletion did not affect platelet aggregation or spreading. When S1pr1 deletion was induced in hematopoietic progenitor cells, platelet counts were instead significantly elevated. Isolated global Sphk2 deficiency was associated with thrombocytopenia, but this was not replicated by MK-restricted Sphk2 deletion and was reversed by compound deletion of either Sphk1 or S1pr2, suggesting that this phenotype arises from increased S1P export and S1P 2 activation secondary to redistribution of sphingosine to Sphk1. Consistent with clinical observations, we thus observe no essential role for S1P 1 in facilitating platelet production or activation. Instead, S1P restricts megakaryopoiesis through S1P 1 , and can further suppress thrombo-poiesis through S1P 2 when aberrantly secreted in the hematopoietic niche.
Published: 2019
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40. Initial seeding of the embryonic thymus by immune-restricted lympho-myeloid progenitors

Author: Tiago C. Luis, Hanane Boukarabila, Adam J. Mead, Harsh J. Vaidya, Isabelle Godin, Charlotta Böiers, Rickard Sandberg, Tiphaine Bouriez-Jones, Supat Thongjuea, Alice Giustacchini, Roger Patient, Sidinh Luc, Joana Carrelha, Frederic Geissmann, Marella F. T. R. de Bruijn, Sten Eirik W. Jacobsen, Petter S. Woll, C. Clare Blackburn, Deborah Atkinson, Emanuele Azzoni, Michael Lutteropp, Takuo Mizukami, Claus Nerlov, Iain C. Macaulay, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Luis, T, Luc, S, Mizukami, T, Boukarabila, H, Thongjuea, S, Woll, P, Azzoni, E, Giustacchini, A, Lutteropp, M, Bouriez-Jones, T, Vaidya, H, Mead, A, Atkinson, D, Böiers, C, Carrelha, J, Macaulay, I, Patient, R, Geissmann, F, Nerlov, C, Sandberg, R, De Bruijn, M, Blackburn, C, Godin, I, and Jacobsen, S
Subjects: 0301 basic medicine, Myeloid, T-Lymphocytes, Cellular differentiation, T cell, Immunology, Notch signaling pathway, Mice, Transgenic, Thymus Gland, Biology, Myeloid Progenitor Cell, Article, Mice, 03 medical and health sciences, Fetus, Cell Movement, medicine, Animals, Immunology and Allergy, Cell Lineage, Fetu, Lymphopoiesis, Cells, Cultured, Myeloid Progenitor Cells, ComputingMilieux_MISCELLANEOUS, Receptors, Notch, Animal, RBPJ, Gene Expression Regulation, Developmental, Cell Differentiation, Lymphoid Progenitor Cells, Embryonic stem cell, Cell biology, Mice, Inbred C57BL, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030104 developmental biology, medicine.anatomical_structure, T-Lymphocyte, Multipotent Stem Cell, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Lymphoid Progenitor Cell, Signal Transduction
Abstract: The final stages of restriction to the T cell lineage occur in the thymus after the entry of thymus-seeding progenitors (TSPs). The identity and lineage potential of TSPs remains unclear. Because the first embryonic TSPs enter a non-vascularized thymic rudiment, we were able to directly image and establish the functional and molecular properties of embryonic thymopoiesis-initiating progenitors (T-IPs) before their entry into the thymus and activation of Notch signaling. T-IPs did not include multipotent stem cells or molecular evidence of T cell-restricted progenitors. Instead, single-cell molecular and functional analysis demonstrated that most fetal T-IPs expressed genes of and had the potential to develop into lymphoid as well as myeloid components of the immune system. Moreover, studies of embryos deficient in the transcriptional regulator RBPJ demonstrated that canonical Notch signaling was not involved in pre-thymic restriction to the T cell lineage or the migration of T-IPs.
Published: 2019
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41. Genomic characterization of metastatic breast cancers

Author: Alexandra Jacquet, Alicia Tran Dien, Thomas Bachelot, Mario Campone, Fabrice Andre, Claudia Lefeuvre, Guillaume Meurice, Salvatore Piscuoglio, Yahia Adnani, Daniel Birnbaum, Florence Dalenc, Hervé Bonnefoi, Maud Kamal, Marta Jimenez, François Bertucci, Max Chaffanet, Charlotte K.Y. Ng, Benjamin Verret, Nadine Carbuccia, Anne Patsouris, Christophe Le Tourneau, Naveen Babbar, Maria R. De Filippo, Thomas Filleron, Semih Dogan, Nathalie Droin, Jean-Charles Soria, Séverine Garnier, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Memorial Sloane Kettering Cancer Center [New York], Senescence Escape and Soluble Markers of Cancer Progression (CRCINA-ÉQUIPE 12), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Gustave Roussy (IGR), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microbiologie : Risques Infectieux, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Faculté de Chirurgie Dentaire de Rennes-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Plateforme de Génomique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UNICANCER [Paris], Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Oncogénèse et progression tumorale, Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, CRLCC Eugène Marquis (CRLCC), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Claudius Regaud, Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Oncologie médicale [Paris], Institut Curie [Paris], Rôle des cellules dendritiques dans la régulation des effecteurs de l'immunité antitumorale, Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Faculté de Chirurgie Dentaire de Rennes-Faculté d'Odontologie-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes - UFR d'Odontologie (UR Odontologie), Université de Rennes (UR)-Université de Rennes (UR), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, AKT1, Breast Neoplasms, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Metastasis, Evolution, Molecular, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Medicine, Humans, Neoplasm Metastasis, skin and connective tissue diseases, Multidisciplinary, business.industry, Genome, Human, GATA3, Genomics, medicine.disease, Metastatic breast cancer, Human genetics, 3. Good health, 030104 developmental biology, Hormone receptor, 030220 oncology & carcinogenesis, Mutation, Cancer research, Disease Progression, Female, business, Estrogen receptor alpha, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Metastasis is the main cause of death for patients with breast cancer. Many studies have characterized the genomic landscape of breast cancer during its early stages. However, there is evidence that genomic alterations are acquired during the evolution of cancers from their early to late stages, and that the genomic landscape of early cancers is not representative of that of lethal cancers1-7. Here we investigated the landscape of somatic alterations in 617 metastatic breast cancers. Nine driver genes (TP53, ESR1, GATA3, KMT2C, NCOR1, AKT1, NF1, RIC8A and RB1) were more frequently mutated in metastatic breast cancers that expressed hormone receptors (oestrogen and/or progesterone receptors; HR+) but did not have high levels of HER2 (HER2-; n = 381), when compared to early breast cancers from The Cancer Genome Atlas. In addition, 18 amplicons were more frequently observed in HR+/HER2- metastatic breast cancers. These cancers showed an increase in mutational signatures S2, S3, S10, S13 and S17. Among the gene alterations that were enriched in HR+/HER2- metastatic breast cancers, mutations in TP53, RB1 and NF1, together with S10, S13 and S17, were associated with poor outcome. Metastatic triple-negative breast cancers showed an increase in the frequency of somatic biallelic loss-of-function mutations in genes related to homologous recombination DNA repair, compared to early triple-negative breast cancers (7% versus 2%). Finally, metastatic breast cancers showed an increase in mutational burden and clonal diversity compared to early breast cancers. Thus, the genomic landscape of metastatic breast cancer is enriched in clinically relevant genomic alterations and is more complex than that of early breast cancer. The identification of genomic alterations associated with poor outcome will allow earlier and better selection of patients who require the use of treatments that are still in clinical trials. The genetic complexity observed in advanced breast cancer suggests that such treatments should be introduced as early as possible in the disease course.
Published: 2019
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42. Beyond the tumour microenvironment

Author: Dorothée Duluc, Lucie Laplane, Nicolas Larmonier, Thomas Pradeu, Andreas Bikfalvi, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut d'Histoire et de Philosophie des Sciences et des Techniques (IHPST), Université Paris 1 Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS), Immunology from Concept and Experiments to Translation (ImmunoConcept), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Mecanismes Moleculaires de l'Angiogenese, Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Laplane, Lucie, Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)
Subjects: Cancer Research, Carcinogenesis, Mini Review, [SDV]Life Sciences [q-bio], education, microbiome, Antineoplastic Agents, [SHS.HISPHILSO]Humanities and Social Sciences/History, Philosophy and Sociology of Sciences, 03 medical and health sciences, 0302 clinical medicine, [SHS.HISPHILSO] Humanities and Social Sciences/History, Philosophy and Sociology of Sciences, Neoplasms, Tumor Microenvironment, medicine, Animals, Humans, ComputingMilieux_MISCELLANEOUS, Cognitive science, nervous system, Cancer, medicine.disease, Gastrointestinal Microbiome, 3. Good health, [SDV] Life Sciences [q-bio], Disease Models, Animal, immune system, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Disease Progression, tumour organismal environment, sense organs, Cancer development, Erratum, tumour microenvironment
Abstract: In contrast to the once dominant tumour-centric view of cancer, increasing attention is now being paid to the tumour microenvironment (TME), generally understood as the elements spatially located in the vicinity of the tumour. Thinking in terms of TME has proven extremely useful, in particular because it has helped identify and comprehend the role of nongenetic and noncell-intrinsic factors in cancer development. Yet some current approaches have led to a TME-centric view, which is no less problematic than the former tumour-centric vision of cancer, insofar as it tends to overlook the role of components located beyond the TME, in the 'tumour organismal environment' (TOE). In this minireview, we highlight the explanatory and therapeutic shortcomings of the TME-centric view and insist on the crucial importance of the TOE in cancer progression.
Published: 2019
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43. Towards a classification of stem cells

Author: Lucie Laplane, Eric Solary, Institut d'Histoire et de Philosophie des Sciences et des Techniques (IHPST), Université Paris 1 Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS), Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Laplane, Lucie, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)
Subjects: 0301 basic medicine, cancer stem cells, QH301-705.5, Science, Classification scheme, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cell fate determination, Biology, Regenerative medicine, General Biochemistry, Genetics and Molecular Biology, [SHS.HISPHILSO]Humanities and Social Sciences/History, Philosophy and Sociology of Sciences, 03 medical and health sciences, 0302 clinical medicine, Cancer stem cell, stem cells, [SHS.HISPHILSO] Humanities and Social Sciences/History, Philosophy and Sociology of Sciences, Stemness, Biology (General), [SDV.BC] Life Sciences [q-bio]/Cellular Biology, cell fate, General Immunology and Microbiology, General Neuroscience, philosophy of biology, Feature Article, General Medicine, Stem Cells and Regenerative Medicine, Cancer treatment, Philosophy of biology, 030104 developmental biology, Phenotype, 030220 oncology & carcinogenesis, philosophy of science, Medicine, Stem cell, Neuroscience
Abstract: International audience; The characteristic properties of stem cells-notably their ability to self-renew and to differentiate-have meant that they have traditionally been viewed as distinct from most other types of cells. However, recent research has blurred the line between stem cells and other cells by showing that the former display a range of behaviors in different tissues and at different stages of development. Here, we use the tools of metaphysics to describe a classification scheme for stem cells, and to highlight what their inherent diversity means for cancer treatment.
Published: 2019
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44. Opinion: Why science needs philosophy

Author: Laplane, Lucie, Mantovani, Paolo, Adolphs, Ralph, Chang, Hasok, Mantovani, Alberto, Mcfall-Ngai, Margaret, Rovelli, Carlo, Sober, Elliott, Pradeu, Thomas, Institut d'Histoire et de Philosophie des Sciences et des Techniques (IHPST), Université Paris 1 Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Science and Technology Studies [London] (STS), University College of London [London] (UCL), Department of Immunology and Cell Biology, Mario Negri Institute, CPT - E4 Gravité quantique, Centre de Physique Théorique - UMR 7332 (CPT), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Immunology from Concept and Experiments to Translation (ImmunoConcept), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, and Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SHS.HISPHILSO]Humanities and Social Sciences/History, Philosophy and Sociology of Sciences, Opinion, [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2019
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45. In vitro and in vivo efficacy of an anti-CD203c conjugated antibody (AGS-16C3F) in mouse models of advanced systemic mastocytosis

Author: Fawzia Louache, Ghaith Wedeh, Yanyan Zhang, Hosein Kouros-Mehr, Florian Beghi, Michel Arock, Viviane Baral, Liang He, Fernando Doñate, Siham Bibi, Jean-Marie Launay, Monika Wittner, Institut Gustave Roussy (IGR), Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de biochimie INSERM UMR-S942, and Hôpital Lariboisière-APHP
Subjects: Immunoconjugates, Immunobiology and Immunotherapy, Apoptosis, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mice, SCID, Antibodies, Monoclonal, Humanized, Cell Line, 03 medical and health sciences, Mice, 0302 clinical medicine, Mastocytosis, Systemic, In vivo, Mice, Inbred NOD, Cytotoxic T cell, Medicine, Animals, Humans, Systemic mastocytosis, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cell Proliferation, 0303 health sciences, Severe combined immunodeficiency, business.industry, Hematology, medicine.disease, 3. Good health, Leukemia, 030220 oncology & carcinogenesis, Monoclonal, Cancer cell, Cancer research, Mast cell sarcoma, business
Abstract: Antibody-drug conjugates (ADCs) are a new class of therapeutics that use antibodies to deliver potent cytotoxic drugs selectively to cancer cells. CD203c, an ecto-nucleotide pyrophosphatase-phosphodiesterase 3, is overexpressed on neoplastic mast cells (MCs) in systemic mastocytosis (SM), thus representing a promising target for antibody-mediated therapy. In this study, we have found that human neoplastic MC lines (ROSAKIT D816V and ROSAKIT D816V-Gluc), which express high levels of CD203c, are highly and specifically sensitive to the antiproliferative effects of an ADC against CD203c (AGS-16C3F). In these cell lines, AGS-16C3F induced cell apoptosis at very low concentrations. To characterize the effects of AGS-16C3F on leukemia progression in vivo, ROSAKIT D816V-Gluc NOD-SCID γ mouse models of advanced SM (AdvSM) were treated with AGS-16C3F or an ADC control for 2 weeks. Whereas AGS-16C3F had no apparent toxicity in xenotransplanted mice, in vivo neoplastic MC burden significantly decreased in both hematopoietic and nonhematopoietic organs. Furthermore, animals treated with AGS-16C3F had prolonged survival compared with the animals treated with control ADC, and AGS-16C3F efficiently prevented disease relapse. In conclusion, these preclinical studies identified CD203c as a novel therapeutic target on neoplastic MCs, and AGS-16C3F as a promising ADC for the treatment of patients with AdvSM.
Published: 2019
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46. TET2-mediated 5-hydroxymethylcytosine induces genetic instability and mutagenesis

Author: Lise Secardin, William Vainchenker, Olivier Bernard, Alexander A. Ishchenko, Murat Saparbaev, Emna Mahfoudhi, Philippe Rameau, Véronique Della Valle, Ibtissam Talhaoui, Isabelle Plo, Xenia Cabagnols, Salem Abbes, Hématopoïèse normale et pathologique (UMR 1170 ), Université Paris-Sud - Paris 11 (UP11) - Institut Gustave Roussy (IGR) - Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'hématologie moléculaire et cellulaire, institut Pasteur de Tunis, Institut Pasteur de Tunis - Réseau International des Instituts Pasteur, Institut Gustave Roussy (IGR), Réparation de l’ADN (CNRS UMR 8200), This work was supported by grants from Agence Nationale de la Recherche (ANR-Blanc 2013 GERMPN) to IP and [ANR Blanc 2010 Project ANR-10-BLAN-1617] to IP and MS, Association pour la Recherche contre le Cancer (ARC) (ARC libre 2012) to IP, Electricité de France (http://www.edf.fr) RB 2014-26 to MS and Fondation de France (http://www.fondationdefrance.org) [#2012 00029161] to AAI. Labex GR-Ex (IP, WV) is funded by the program 'Investissements d’avenir'. EM was funded by INSERM/DGRST then a grant from Institut Pasteur from Tunis, Tunisia. LS were supported by Ph.D grants from the Cancéropôle Région Ile de France (DIM cellule souche). XC was supported by Ph.D MENRT grant. IT was supported by postdoctoral fellowship from the Fondation ARC (http://www.arc-cancer.net) PDF20110603195., ANR-Blanc 2013 GERMPN, GERMPN, ANR-10-BLAN-1617, EPIGENOME, Formation, dynamics and epigenetic functions of 5-hydroxymethylcytosine residues in DNA.(2010), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tunis El Manar (UTM), Laboratoire d'hématologie moléculaire et cellulaire (LR11IPT07), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Plateforme imagerie et cytométrie (PFIC), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Hématologie, Institut Pasteur de Tunis, This work was supported by grants from Agence Nationale de la Recherche (ANR-Blanc 2013 GERMPN) to IP and [ANR Blanc 2010 Project ANR-10-BLAN-1617] to IP and MS, Association pour la Recherche contre le Cancer (ARC) (ARC libre 2012) to IP, Electricité de France (http://www.edf.fr) RB 2014-26 to MS and Fondation de France (http://www.fondationdefrance.org) [#2012 00029161] to AAI. Labex GR-Ex (IP, WV) is funded by the program 'Investissements d’avenir'. EM was funded by INSERM/DGRST then a grant from Institut Pasteur from Tunis, Tunisia. LS were supported by Ph.D grants from the Cancéropôle Région Ile de France (DIM cellule souche). XC was supported by Ph.D MENRT grant. IT was supported by postdoctoral fellowship from the Fondation ARC., We thank the cytometry platform of Gustave Roussy (Y. Lecluse)., ANR-10-BLAN-1617,EPIGENOME,Formation, dynamics and epigenetic functions of 5-hydroxymethylcytosine residues in DNA.(2010), ANR-13-JSV1-0007,GERMPN,Etude des cas familiaux de néoplasmes myéloproliférifs: recherche des anomalies génétiques et de leurs fonctions.(2013), Pasteur Tunis, Institut, BLANC - Formation, dynamics and epigenetic functions of 5-hydroxymethylcytosine residues in DNA. - - EPIGENOME2010 - ANR-10-BLAN-1617 - BLANC - VALID, Jeunes Chercheuses et Jeunes Chercheurs - Etude des cas familiaux de néoplasmes myéloproliférifs: recherche des anomalies génétiques et de leurs fonctions. - - GERMPN2013 - ANR-13-JSV1-0007 - JC - VALID, and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, DNA Repair, Genetic instability, MESH: Fibroblasts/cytology, MESH: Tumor Suppressor Protein p53/metabolism, MESH: Fibroblasts/metabolism, MESH: Mutagenesis, MESH: Base Sequence, MESH: Thymine DNA Glycosylase/deficiency, Biochemistry, MESH: DNA Repair, Epigenesis, Genetic, S Phase, MESH: Thymine DNA Glycosylase/genetics, Mice, chemistry.chemical_compound, MESH: Genomic Instability, MESH: DNA-Binding Proteins/genetics, MESH: B-Lymphocytes/metabolism, MESH: Animals, MESH: Cytosine/metabolism, MESH: Epigenesis, Genetic, MESH: Megakaryocyte Progenitor Cells/cytology, MESH: B-Lymphocytes/cytology, B-Lymphocytes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Cytosine/analogs & derivatives, MESH: S Phase, Base excision repair, DNA-Binding Proteins, MESH: Proto-Oncogene Proteins/genetics, 5-hmC, CpG site, 5-Methylcytosine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cytosine, Guanine, MESH: Hydroxylation, TDG, Cell cycle, Biology, MESH: DNA-Binding Proteins/metabolism, Hydroxylation, Genomic Instability, Cell Line, Dioxygenases, 03 medical and health sciences, MESH: Tumor Suppressor Protein p53/genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Proto-Oncogene Proteins, Animals, Humans, MESH: Mice, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Megakaryocyte Progenitor Cells, MESH: 5-Methylcytosine/analogs & derivatives, 5-Hydroxymethylcytosine, TET2, MESH: Humans, Base Sequence, MESH: Proto-Oncogene Proteins/metabolism, Mutagenesis, MESH: 5-Methylcytosine/metabolism, Cell Biology, Fibroblasts, Molecular biology, Thymine DNA Glycosylase, MESH: Cell Line, 030104 developmental biology, DNA demethylation, chemistry, DNA glycosylase, MESH: Megakaryocyte Progenitor Cells/metabolism, Tumor Suppressor Protein p53
Abstract: International audience; The family of Ten-Eleven Translocation (TET) proteins is implicated in the process of active DNA demethy-lation and thus in epigenetic regulation. TET 1, 2 and 3 proteins are oxygenases that can hydroxylate 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) and further oxidize 5-hmC into 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC). The base excision repair (BER) pathway removes the resulting 5-fC and 5-caC bases paired with a guanine and replaces them with regular cytosine. The question arises whether active modification of 5-mC residues and their subsequent elimination could affect the genomic DNA stability. Here, we generated two inducible cell lines (Ba/F3-EPOR, and UT7) over-expressing wild-type or catalytically inactive human TET2 proteins. Wild-type TET2 induction resulted in an increased level of 5-hmC and a cell cycle defect in S phase associated with higher level of phospho-rylated P53, chromosomal and centrosomal abnormalities. Furthermore, in a thymine-DNA glycosylase (Tdg) deficient context, the TET2-mediated increase of 5-hmC induces mutagenesis characterized by GC > AT transitions in CpG context suggesting a mutagenic potential of 5-hmC metabolites. Altogether, these data suggest that TET2 activity and the levels of 5-hmC and its derivatives should be tightly controlled to avoid genetic and chromosomal instabilities. Moreover, TET2-mediated active demethylation might be a very dangerous process if used to entirely demethylate the genome and might rather be used only at specific loci.
Published: 2016
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47. Gain of the short arm of chromosome 2 (2p gain) has a significant role in drug‐resistant chronic lymphocytic leukemia

Author: Kostopoulou, Fotini, Gabillaud, Clementine, Chapiro, Elise, Grange, Beatrice, Tran, Julie, Bouzy, Simon, Degaud, Michael, Ghamlouch, Hussein, Le Garff‐Tavernier, Magali, Maloum, Karim, Choquet, Sylvain, Leblond, Veronique, Gabarre, Jean, Lavaud, Anne, Morel, Veronique, Roos‐Weil, Damien, Uzunov, Madalina, Guieze, Romain, Bernard, Olivier A., Susin, Santos A., Tournilhac, Olivier, Nguyen‐Khac, Florence, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut Gustave Roussy (IGR), Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École pratique des hautes études (EPHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Adult, Male, Immunoglobulin Variable Region, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polymorphism, Single Nucleotide, Immunophenotyping, Time-to-Treatment, [SDV.CAN] Life Sciences [q-bio]/Cancer, Recurrence, immune system diseases, hemic and lymphatic diseases, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Antineoplastic Combined Chemotherapy Protocols, Chromosome Duplication, Humans, Longitudinal Studies, Protein Kinase Inhibitors, In Situ Hybridization, Fluorescence, Original Research, Cancer Biology, Aged, Chromosome Aberrations, drug resistance, 2p gain, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Middle Aged, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell, Treatment Outcome, Drug Resistance, Neoplasm, Chromosomes, Human, Pair 2, Karyotyping, Mutation, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], chronic lymphocytic leukemia, Female
Abstract: International audience; The different types of drug resistance encountered in chronic lymphocytic leukemia (CLL) cannot be fully accounted for by the 17p deletion (and/or TP53 mutation), a complex karyotype (CK), immunoglobulin heavy-chain variable region genes (IGHV) status and gene mutations. Hence, we sought to assess the associations between recurrent genomic abnormalities in CLL and the disease's development and outcome. To this end, we analyzed 64 samples from patients with CLL and gain of the short arm of chromosome 2 (2p+), which is frequent in late-stage and relapsed/refractory CLL. We found that fludarabine/cyclophosphamide/rituximab (a common first-line treatment in CLL) is not effective in removing the 2p+ clone - even in samples lacking a CK, the 17p deletion or unmutated IGHV. Our results suggest strongly that patients with CLL should be screened for 2p+ (using karyotyping and fluorescence in situ hybridization) before a treatment option is chosen. Longer follow-up is now required to evaluate bendamustine-rituximab, ibrutinib, and idelalisib-rituximab treatments.
Published: 2019
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48. Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging

Author: Cristina González-Gómez, Claudia Korn, Randall S. Johnson, Carlos López-Otín, Justyna Rak, Amie K. Waller, William Vainchenker, Fawzia Louache, Monika Wittner, Claus Nerlov, Alberto del Monte, Simón Méndez-Ferrer, Raquel del Toro, José Rivera-Torres, Ya-Hsuan Ho, Cedric Ghevaert, David Macías, Holly R. Foster, Vicente Andrés, Andrés García-García, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidad de Oviedo [Oviedo], University of Oxford [Oxford], Hematopoïèse et Cellules Souches (U362), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), University of Cambridge, Fundación Ramón Areces, Fundación 'la Caixa', European Commission, Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad (España), Ministerio de Economía y Competitividad (España), Fundació La Marató de TV3, Progeria Research Foundation, Wellcome Trust, Comunidad de Madrid, National Health Institute Blood and Transplant (UK), Cancer Research UK, Howard Hughes Medical Institute, University of Cambridge (Reino Unido), Fundación La Caixa, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Fundacio La Marato, Fundación ProCNIC, Ministerio de Ciencia, Innovación y Universidades (España), Comunidad de Madrid (España), NHS - Blood and Transplant (Reino Unido), European Research Council, Waller, Amie [0000-0002-9726-5560], Johnson, Randall [0000-0002-4084-6639], Ghevaert, Cedric [0000-0002-9251-0934], and Apollo - University of Cambridge Repository
Subjects: Myeloid, Aging, Envejecimiento, Nitric Oxide Synthase Type I, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Lymphoid, Hematopoietic stem cell, Mice, Progeria, 0302 clinical medicine, Megakaryocyte, Bone Marrow, Myeloid Cells, Stem Cell Niche, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Movilización de célula madre hematopoyética, Hutchinson-Gilford progeria, Aging, Premature, Cell Differentiation, Cell Encapsulation, Adrenergic Agonists, Cell biology, niche, Haematopoiesis, medicine.anatomical_structure, Physiological Aging, Molecular Medicine, Myelopoiesis, myeloid, Stem cell, Megakaryocytes, Signal Transduction, Nicho de células madre, Premature aging, Microenvironment, lymphoid, education, Biology, 03 medical and health sciences, Niche, Genetics, medicine, Animals, Humans, Cell Proliferation, 030304 developmental biology, Megakaryopoiesis, Biología celular, Interleukin-6, Cell Biology, Hematopoietic Stem Cells, microenvironment, Efectos fisiológicos, Disease Models, Animal, hematopoietic stem cell, Receptors, Adrenergic, beta-2, 030217 neurology & neurosurgery
Abstract: Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes β2-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β3-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β3-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment., Y.-H.O. received fellowships from Alborada Scholarship (University of Cambridge), Trinity-Henry Barlow Scholarship (University of Cambridge), and R.O.C. Government Scholarship to Study Abroad (GSSA). A.G.G. received fellowships from the Ramón Areces Foundation and the LaCaixa Foundation. C.K. was supported by Marie Curie Career Integration (H2020-MSCA-IF-2015-70841). S.M.-F. was supported by Red TerCel (ISCIII-Spanish Cell Therapy Network). V.A. is supported by grants from the Spanish Ministerio de Economía, Industria y Competitividad (MEIC) with cofunding from the Fondo Europeo de Desarrollo Regional (FEDER, “Una manera de hacer Europa”) (SAF2016-79490-R), the Instituto de Salud Carlos III (AC16/00091 and AC17/00067), the Fundació Marató TV3 (122/C/2015), and the Progeria Research Foundation (Established Investigator Award 2014–52). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCIU), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). This work was supported by core support grants from the Wellcome Trust and the MRC to the Cambridge Stem Cell Institute, MEIC (SAF-2011-30308), Ramón y Cajal Program Grant (RYC-2009-04703), ConSEPOC-Comunidad de Madrid (S2010/BMD-2542), National Health Service Blood and Transplant (United Kingdom), European Union’s Horizon 2020 research (ERC-2014-CoG-64765 and Marie Curie Career Integration grant FP7-PEOPLE-2011-RG-294096), and a Programme Foundation Award from Cancer Research UK to S.M.-F., who was also supported in part by an International Early Career Scientist grant from the Howard Hughes Medical Institute.
Published: 2019
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49. Ontogenic changes in hematopoietic hierarchy determine pediatric specificity and disease phenotype in fusion oncogene-driven myeloid leukemia

Author: Cécile K. Lopez, Marie Laure Arcangeli, Eric Delabesse, Sébastien Malinge, Alexandre Fagnan, Isabelle Godin, Franco Locatelli, Françoise Pflumio, Fabien Boudia, Cécile Thirant, Muriel Gaudry, Vaia Stavropoulou, Arnaud Petit, Claus Nerlov, Nathalie Droin, Riccardo Masetti, Paola Ballerini, Zakia Aid, Berthold Göttgens, Olivier Bernard, Sarah Kinston, Erika Brunet, Hélène Lapillonne, Loelia Babin, Juerg Schwaller, Antoine H.F.M. Peters, Elie Robert, Yann Lécluse, Bastien Job, Chrystele Bilhou-Nabera, Jean-Luc Villeval, Camille Lobry, William Vainchenker, Thomas Mercher, Esteve Noguera, M'Boyba Diop, Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de Bioinformatique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bases fondamentales et stratégies nouvelles en cancérologie (BFSNC - IFR54), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Régulation et dynamique des génomes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Santa Lucia Foundation, IRCSS, Rome, University of Oxford [Oxford], Images et Modèles, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Cambridge [UK] (CAM), Service Procédés et Innovations Industriels (SPII), eRcane, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique des tumeurs (U985), Institut Gustave Roussy (IGR)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche et d'Etude en Droit et Science Politique (CREDESPO), Université de Bourgogne (UB), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lopez C.K., Noguera E., Stavropoulou V., Robert E., Aid Z., Ballerini P., Bilhou-Nabera C., Lapillonne H., Boudia F., Thirant C., Fagnan A., Arcangeli M.-L., Kinston S.J., Diop M., Job B., Lecluse Y., Brunet E., Babin L., Villeval J.L., Delabesse E., Peters A.H.F.M., Vainchenker W., Gaudry M., Masetti R., Locatelli F., Malinge S., Nerlov C., Droin N., Lobry C., Godin I., Bernard O.A., Gottgens B., Petit A., Pflumio F., Schwaller J., Mercher T., Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire d'Hématologie [AP-HP Hôpital Armand Trousseau], Cellules Souches et Radiations (SCSR (U967 / UMR-E_008)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Brunet, Erika [0000-0002-1726-4673], Malinge, Sébastien [0000-0002-9533-7778], Droin, Nathalie [0000-0002-6099-5324], Godin, Isabelle [0000-0001-8577-8388], Göttgens, Berthold [0000-0001-6302-5705], Schwaller, Juerg [0000-0001-8616-0096], Mercher, Thomas [0000-0003-1552-087X], Apollo - University of Cambridge Repository, Centre de Psychiatrie et Neurosciences (U894), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Myeloid, Oncogene Proteins, Fusion, Oncogene Proteins, Fusion gene, Mice, 0302 clinical medicine, AML, CEBPA, GENOMIC ALTERATIONS, Tumor Cells, Cultured, TRANSCRIPTION FACTOR, RNA-SEQ, Child, ComputingMilieux_MISCELLANEOUS, GENE-EXPRESSION, Age Factors, Myeloid leukemia, GATA1, 3. Good health, Leukemia, Myeloid, Acute, Leukemia, Haematopoiesis, medicine.anatomical_structure, DIFFERENTIATION, Oncology, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Child, Preschool, 030220 oncology & carcinogenesis, Female, Adolescent, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, children, ACUTE MEGAKARYOBLASTIC LEUKEMIA, transcription factors, medicine, Animals, Humans, FETAL, pediatric acute myeloid leukemia, LINEAGE COMMITMENT, Infant, medicine.disease, STEM-CELL, SELF-RENEWAL, 030104 developmental biology, Cancer research, Neoplasm Transplantation
Abstract: Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as ETO2–GLIS2, are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2–GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2–GLIS2-induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. Significance: This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state. See related commentary by Cruz Hernandez and Vyas, p. 1653. This article is highlighted in the In This Issue feature, p. 1631
Published: 2019
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50. Role of Confinement on Clathrin-mediated Endocytosis

Author: Le devedec, Dahiana, STAR, ABES, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Saclay (COmUE), and Guillaume Montagnac
Subjects: Récepteur à l'EGF, Frustrated endocytosis, [SDV.CAN] Life Sciences [q-bio]/Cancer, Hb-Egf, Egfr, Clathrine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Endocytose frustrée, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Clathrin, Confinement
Abstract: Clathrin-mediated endocytosis (CME) is the major route of endocytosis for many cargos in eukaryotic cells. Endocytosis takes place at clathrin-coated pits (CCPs), small assemblies of clathrin and clathrin adaptors randomly distributed at the plasma membrane. Clathrin polymerization induces the progressive bending of the plasma membrane resulting in the formation of a vesicle budding off into the cytosol. CME is a highly dynamic process with an average lifetime of CCPs in the order of 30 seconds. In this manner, CME fulfills a range of different functions and enables cells to regulate the surface expression of proteins, to sample the cell’s environment for growth and guidance cues, to control the activation of signaling pathways and to turn over membrane components by sending these components for degradation in the endo-lysosomal pathway. A deregulation of the endocytic pathways was previously shown to be involve in cancer. These modifications can affect CME directly by modifying its actors, or indirectly with mutations on receptors or cargoes undertaken by CME. Tumor progression is dependent of several factors, the first one involving the accumulation of mutations which results in modifications in the cells themselves or on their surrounding environment by changing its biochemical and physical properties, leading to the formation of the tumor niche. These changes reciprocally foster cancer progression. During tumor growth, fibroblasts will be recruited around tumor cells, leading to the remodeling of the microenvironment and to an increase of rigidity nearby the tumor. This stiffness is sensed by the cells and send signals for proliferation and migration as a result. Stiffness sensing engages mainly integrins at the cell surface which will aggregate and initiate signaling cascades accountable for these responses. Integrins are capable of clustering into two types of structures: focal adhesions and clathrin-coated structures (CCSs). Regarding CCSs, it was shown previously that high stiffness strengthen the interaction between integrins and the substrate, hence preventing the budding off of the vesicle, and this is referred to as “frustrated endocytosis”. This holding of CCSs at the cell surface promotes a sustained signaling at the plasma membrane instead of a signal termination after internalization and further degradation in lysosomes. My PhD project relied on these previous findings, with a particular focus on another mechanical alteration observed in tumors, the confinement. Indeed, during the uncontrolled proliferation of cancer cells in a spatially restricted area, cells become subjected to compressive forces. The results I obtained indicate that confinement leads to frustrated endocytosis and hence to sustained signaling from the plasma membrane. In addition, compression also leads to HB-EGF shedding at the cell surface, and the resulting EGF product activate the EGFR in a paracrine manner, thus leading to the activation of the MAP kinase Erk signaling pathway. Indeed, both the absence of EGFR ligands in the medium and the inhibition of the shedding demonstrate the necessity of this mechanism in EGFR activation. To sum up, confinement induces the shedding of the EGFR pro-ligand HB-EGF necessary to EGFR activation in these conditions. Simultaneously, endocytosis is delayed and frustrated endocytosis leads to sustained signaling at the cell surface. Together, these events cooperate to strongly activate the Erk pathway. These findings highlight the interplay between the physical feature of the tumor environment and signaling pathways known to govern tumor growth., L’endocytose dépendante de la clathrine (EDC) est la principale voie d’internalisation des récepteurs de surface et de leurs ligands. L’internalisation se fait suite à l’invagination de la membrane plasmique vers l’intérieur de la cellule suite à la formation, dans un premier temps, de puits recouverts de clathrine (PRCs) qui bourgeonnent ensuite en vésicules recouvertes de clathrine dans le cytosol. L’EDC est un processus très dynamique qui a lieu en l’espace de 30 sec-1mn. Elle est impliquée dans de multiples fonctions et permet ainsi à la cellule de réguler l’expression de ses protéines en surface, de répondre aux signaux de prolifération ou migration envoyés par l’environnement immédiat via l’activation de voies de signalisation spécifiques ou encore de réguler le renouvellement des composants de la membrane plasmique. De par son importance, des dérégulations de l’endocytose dépendante de la clathrine ont déjà été observées dans les cancers. Ces modifications peuvent impliquer directement l’EDC en modifiant ses composants ou indirectement lors d’altérations de récepteurs régulés par celle-ci. La progression tumorale est elle-même régulée par de multiples facteurs, notamment l’accumulation de mutations qui ont des conséquences sur les cellules cancéreuses elle-même ou bien sur l’environnement immédiat, formant ainsi la « niche tumorale ». Ces changements agissent réciproquement sur la progression tumorale afin de l’amplifier. Lors de la croissance tumorale, les cellules cancéreuses recrutent des fibroblastes qui vont participer au remodelage et à l’augmentation de la rigidité autour de la tumeur. La rigidité de la matrice extracellulaire est détectée par les cellules ce qui envoie des signaux déclencheurs de prolifération et de migration en conséquence. Cette détection passe essentiellement par les intégrines à la surface membranaire qui vont s’agréger et induire des cascades de signalisation impliquées dans ces réponses. Ces intégrines peuvent se regrouper dans deux types de structures, les adhésions focales et les structures recouvertes de clathrine. En ce qui concerne ces dernières, il a été démontré précédemment que la rigidité du substrat augmente sa force d’interaction avec les intégrines, et empêche ainsi l’internalisation des vésicules recouvertes de clathrine, on parle alors d’ « endocytose frustrée ». Cette rétention des structures recouvertes de clathrine à la surface provoque une signalisation soutenue à la surface au lieu de l’arrêter par dégradation ultérieure des récepteurs dans les lysosomes. Le laboratoire a démontré que les structures de clathrine frustrées capturent ainsi différent récepteurs conduisant à une signalisation accrue dans la voie de la MAP Kinase Erk. Mon projet de thèse repose sur ces observations en s’intéressant plus particulièrement au rôle d’une autre modification induite par la croissance tumorale, le confinement. En effet, en se multipliant de manière incontrôlée dans un environnement spatialement restreint, les cellules tumorales se retrouvent soumises à des forces de compression. Les résultats mis en évidence au cours de ma thèse ont montré que le confinement provoque, comme la rigidité, une frustration des structures de clathrine qui ne sont donc plus capables de soutenir l’endocytose des récepteurs. De plus, la compression cellulaire induit le clivage d’un pro-ligand de l’EGFR, le HB-EGF, ce qui conduit à l’activation paracrine de l’EGFR et à l’activation de la voie Erk. En effet, l’absence de facteurs de croissance dans le milieu ainsi que l’inhibition de ce clivage démontrent la nécessité de la mise en place de ce mécanisme. En résumé, le confinement induit le clivage du pro-ligand HB-EGF, qui à son tour va activer le récepteur à l’EGF. En parallèle, l’endocytose est ralentie et provoque une signalisation accrue à la membrane. Ces deux évènements coopèrent pour mener à une très forte activation de la voie Erk.
Published: 2019

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