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1. 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

2. Inferring the dynamic of mutated hematopoietic stem and progenitor cells induced by IFNα in myeloproliferative neoplasms

Author

Cécile Le Sueur, François Girodon, Matthieu Mosca, Stefan N. Constantinescu, Cyril Catelain, Rémi Favier, Hana Raslova, Julien Lenglet, Bruno Cassinat, Robert Noble, Christophe Marzac, Hugo Campario, Florence Pasquier, Philippe Rameau, Caroline Marty, Amandine Tisserand, Gurvan Hermange, Cyril Gella, Isabelle Plo, Gaëlle Vertenoeil, Paul-Henry Cournède, Mira El-Khoury, Jean-Jacques Kiladjian, Jean-Luc Villeval, William Vainchenker, Eric Solary, Michael E. Hochberg, Nicole Casadevall, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Mathématiques et Informatique pour la Complexité et les Systèmes (MICS), CentraleSupélec-Université Paris-Saclay, Institute of Evolutionary Biology and Environmental Studies, Zurich University, Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Ludwig Institute for Cancer Research, Université Catholique de Louvain = Catholic University of Louvain (UCL), 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), Hôpital Privé d'Antony, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris Cité (UPCité), and ANR-18-IBHU-0002,PRISM,PRecISion Medicine Institute in oncology(2018)

Subjects
[SDV]Life Sciences [q-bio], Immunology, Alpha interferon, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], Tumor Cells, Cultured, Humans, Immunologic Factors, Longitudinal Studies, Prospective Studies, Progenitor cell, QA, Gene, 030304 developmental biology, Thrombopoietin receptor, 0303 health sciences, Myeloproliferative Disorders, biology, Interferon-alpha, Cell Biology, Hematology, Janus Kinase 2, Hematopoietic Stem Cells, 3. Good health, Haematopoiesis, 030220 oncology & carcinogenesis, Molecular Response, Mutation, biology.protein, Cancer research, Stem cell, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Calreticulin, Receptors, Thrombopoietin
Abstract

Classical BCR-ABL–negative myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells (HSCs) caused mainly by recurrent mutations in genes encoding JAK2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL). Interferon α (IFNα) has demonstrated some efficacy in inducing molecular remission in MPNs. To determine factors that influence molecular response rate, we evaluated the long-term molecular efficacy of IFNα in patients with MPN by monitoring the fate of cells carrying driver mutations in a prospective observational and longitudinal study of 48 patients over more than 5 years. We measured the clonal architecture of early and late hematopoietic progenitors (84 845 measurements) and the global variant allele frequency in mature cells (409 measurements) several times per year. Using mathematical modeling and hierarchical Bayesian inference, we further inferred the dynamics of IFNα-targeted mutated HSCs. Our data support the hypothesis that IFNα targets JAK2V617F HSCs by inducing their exit from quiescence and differentiation into progenitors. Our observations indicate that treatment efficacy is higher in homozygous than heterozygous JAK2V617F HSCs and increases with high IFNα dose in heterozygous JAK2V617F HSCs. We also found that the molecular responses of CALRm HSCs to IFNα were heterogeneous, varying between type 1 and type 2 CALRm, and a high dose of IFNα correlates with worse outcomes. Our work indicates that the long-term molecular efficacy of IFNα implies an HSC exhaustion mechanism and depends on both the driver mutation type and IFNα dose.

Published
2021

3. Genomic analysis of primary and secondary myelofibrosis redefines the prognostic impact of ASXL1 mutations: a FIM study

Author

Jean-Claude Chomel, Jean-Christophe Ianotto, Laurane Cottin, Pierre Sujobert, Véronique Mansat-De Mas, Barbara Burroni, Vincent Cussac, Nathalie Jézéquel, Brigitte Dupriez, Bruno Cassinat, Emmanuelle Verger, Raouf Ben Abdelali, Dana Ranta, Damien Luque Paz, Olivier Kosmider, Olivier Mansier, Gabriel Etienne, Jerome Rey, Maxime Renard, Jean-Jacques Kiladjian, Fabienne Vacheret, Guillaume Denis, Anne Murati, Jérémie Riou, Pascal Mossuz, Françoise Boyer, Eric Lippert, Yannick Le Bris, Pascale Cony-Makhoul, Ivan Sloma, Anouk Walter-Petrich, Suzanne Tavitian, Stéphane Giraudier, Stéphane Girault, Aurélie Chauveau, Gérard Socié, François Girodon, Lydia Roy, Olivier Nibourel, Borhane Slama, Valérie Ugo, Margot Robles, Mathieu Wemeau, Bernardo, Elizabeth, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), 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), Service d'hématologie [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), UFR Santé [UNIV Angers], Université d'Angers (UA), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), 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), Laboratoire de Biologie Cellulaire [AP-HP Hôpital 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), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d'hématologie clinique [CHRU Brest], Service d'hématologie clinique [CH Lens], Centre Hospitalier de Lens, Service des maladies du sang [Angers], Service d'Hématologie [Bordeaux], CHU Bordeaux [Bordeaux], Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Immuno-hématologie clinique [Hôpital Sainte Marguerite - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), 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), Institut Bergonié [Bordeaux], UNICANCER, 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-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Service d'Hématologie [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'hématologie biologique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'Hématologie Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Cancérologie Biologique [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'Hématologie [CH Annecy], CH Annecy, Service d'hématologie biologique [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Perigueux, Laboratoire CERBA [Saint Ouen l'Aumône], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d’Hématologie [CHU Henri-Mondor - APHP], CHU Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire d'Hématologie et d'Immunologie [CHU Henri Mondor], 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 d'Hématologie [CH Perpignan], CH Perpignan, Centre Hospitalier de Roubaix, Service d'hématologie et d'Oncologie [CHU Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Avignon Université (AU), Service d’Onco-Hématologie et Médecine interne [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Centre Hospitalier de Rochefort, Equipe 2 : ECSTRA - Epidémiologie Clinique, STatistique, pour la Recherche en Santé (CRESS - U1153), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département d'anatomopathologie [CHU Cochin], Unité d'hématologie et de transplantation, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], CIC Saint Louis (CIC-1427), 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], 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 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)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-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)-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), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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), Service d'hématologie biologique [CHU de Dijon], CHU Henri Mondor [Créteil], and Centre Hospitalier de Rochefort (CH Rochefort)

Subjects
Neuroblastoma RAS viral oncogene homolog, Oncology, medicine.medical_specialty, IDH1, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease_cause, IDH2, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Myelofibrosis, 030304 developmental biology, 0303 health sciences, Mutation, Acute leukemia, Myeloid Neoplasia, business.industry, Hazard ratio, Bayes Theorem, Hematology, Genomics, medicine.disease, Prognosis, 3. Good health, Repressor Proteins, Primary Myelofibrosis, 030220 oncology & carcinogenesis, KRAS, business
Abstract

We aimed to study the prognostic impact of the mutational landscape in primary and secondary myelofibrosis. The study included 479 patients with myelofibrosis recruited from 24 French Intergroup of Myeloproliferative Neoplasms (FIM) centers. The molecular landscape was studied by high-throughput sequencing of 77 genes. A Bayesian network allowed the identification of genomic groups whose prognostic impact was studied in a multistate model considering transitions from the 3 conditions: myelofibrosis, acute leukemia, and death. Results were validated using an independent, previously published cohort (n = 276). Four genomic groups were identified: patients with TP53 mutation; patients with ≥1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS, or KRAS (high-risk group); patients with ASXL1-only mutation (ie, no associated mutation in TP53 or high-risk genes); and other patients. A multistate model found that both TP53 and high-risk groups were associated with leukemic transformation (hazard ratios [HRs] [95% confidence interval], 8.68 [3.32-22.73] and 3.24 [1.58-6.64], respectively) and death from myelofibrosis (HRs, 3.03 [1.66-5.56] and 1.77 [1.18-2.67], respectively). ASXL1-only mutations had no prognostic value that was confirmed in the validation cohort. However, ASXL1 mutations conferred a worse prognosis when associated with a mutation in TP53 or high-risk genes. This study provides a new definition of adverse mutations in myelofibrosis with the addition of TP53, CBL, NRAS, KRAS, and U2AF1 to previously described genes. Furthermore, our results argue that ASXL1 mutations alone cannot be considered detrimental.

Published
2021

4. Improvement of Standardization of Molecular Analyses in Hematology: The 10-year GBMHM French Experience

Author

Damien Luque-Paz, Sandrine Hayette, Anne Sophie Alary, Jean Michel Cayuela, Claude Preudhomme, Olivier Kosmider, Elizabeth Macintyre, Fanny Baran-Marszak, Marie Hélène Delfau-Larue, Carole Mauté, Bruno Cassinat, Pascale Flandrin-Gresta, Frederic Davi, Eric Lippert, Pierre Sujobert, Audrey Gauthier, Pascale Cornillet-Lefebvre, Gestionnaire, HAL Sorbonne Université 5, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), [Institut Cochin] Département Développement, Reproduction et Cancer (DRC), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), 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), Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], 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), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP, Hôpital Henri-Mondor Albert-Chenevier, Service d'Immunologie Clinique et Maladies Infectieuses 94000 Créteil, France, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), 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), and 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)

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.medical_specialty, Standardization, Article, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Retrospective analysis, medicine, Diseases of the blood and blood-forming organs, Medical physics, Accreditation, business.industry, International standard, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Objective Improvement, 3. Good health, Test (assessment), 030220 oncology & carcinogenesis, RC633-647.5, business, JAK2 V617F, Quality assurance, 030215 immunology
Abstract

International audience; Molecular tests have become an indispensable tool for the diagnosis and prognosis of hematological malignancies and are subject to accreditation according to the International Standard ISO 15189. National standardization of these techniques is essential to ensure that patients throughout France benefit from the same care. We report here on the experience of the GBMHM (Groupe des Biologistes Moléculaires des Hémopathies Malignes). By organizing External Evaluation of Quality (EEQ) programs and training meetings, the GBMHM has contributed to improvement and standardization of molecular tests in 64 French laboratories. A retrospective analysis of the quality-control results of 11 national campaigns spanning 10 years was performed for the 3 most frequently prescribed tests: BCR-ABL1, JAK2 V617F, and lymphoid clonality. For each test, particular attention was placed on comparing methodologies and their evolution throughout the period. The establishment of the BCR-ABL1, JAK2 V617F, and lymphoid clonality EEQ programs and the associated training meetings have initiated a process of collective standardization concerning the methods of implementation (JAK2 V617F) and the interpretation and formulation of results (lymphoid clonality). In addition, it resulted in objective improvement in technical performance (BCR-ABL1). Our evaluation of the impact of these EEQ programs demonstrates that it is possible to obtain reproducible values across different laboratories in France by applying national recommendations. To our knowledge, this is the first publication that evaluates the impact of a national quality assurance program on improving molecular results in hematology.

Published
2021

5. Anemia and hemodilution: analysis of a single center cohort based on 2,858 red cell mass measurements

Author

Juliette Soret-Dulphy, Laetitia Vercellino, Anne C. Brignier, Marie-Helene Schlageter, Louis Drevon, Bruno Cassinat, Célia Belkhodja, Christine Chomienne, Nabih Maslah, Christine Dosquet, Nathalie Parquet, Jean-Jacques Kiladjian, Odno Ravdan, Stéphane Giraudier, leboeuf, Christophe, 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), CIC Saint Louis (CIC-1427), 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], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Hemodilution, medicine.medical_specialty, Red Cell, Anemia, business.industry, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], MEDLINE, Hematology, medicine.disease, Single Center, Cohort Studies, Text mining, Hematocrit, Internal medicine, Cohort, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Letters to the Editor, business, Erythrocyte Volume
Abstract

International audience; No abstract available

Published
2021

6. Long-term follow-up of JAK2 exon 12 polycythemia vera: a French Intergroup of Myeloproliferative Neoplasms (FIM) study

Author

Laurane Cottin, Sylvie Tondeur, Jean-Christophe Ianotto, Olivier Mansier, Lenaïg Le Clech, Jean-Marie Chrétien, Franciane Paul, Mélanie Mercier, Laurent Voillat, Dana Ranta, Benoit de Renzis, Olivier Allangba, François Girodon, Christophe Marzac, Mathilde Hunault-Berger, Valérie Ugo, Corentin Orvain, Driss Chaoui, Jérémie Riou, Eric Lippert, Bruno Cassinat, Jean-Jacques Kiladjian, Suzanne Tavitian, Françoise Boyer, Damien Luque Paz, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut de Biologie et Pathologie [CHU Grenoble] (IBP), CHU Grenoble-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Département d’Hématologie Clinique [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hématologie Clinique [CHI Cornouaille, Quimper], Centre Hospitalier Intercommunal de Cornouaille [Quimper] (CHI Cornouaille [Quimper]), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' [Brest] (FHU GOAL), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'Hématologie [CH Argenteuil], CH Argenteuil, Hématologie Clinique [CH Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), 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, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), 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 d'Hématologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), UFR Santé [UNIV Angers], Université d'Angers (UA), Laboratoire de Biologie Cellulaire [AP-HP Hôpital 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), Cellule de Gestion des Données et Evaluation [CHU Angers] (DRCI - CGDE), Service d'hématologie clinique [CHRU de Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d'Hématologie Clinique [CH Saint-Brieuc], Centre hospitalier Saint-Brieuc, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier Chalon-sur-Saône William Morey, Service des maladies du sang [Angers], Service d'hématologie [Angers], Service d'hématologie biologique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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), Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-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)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
Adult, Male, Cancer Research, Pediatrics, medicine.medical_specialty, Long term follow up, MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cohort Studies, 03 medical and health sciences, Exon, 0302 clinical medicine, Polycythemia vera, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biomarkers, Tumor, medicine, Humans, article clinique, Polycythemia Vera, ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, 0303 health sciences, Myeloproliferative Disorders, business.industry, Exons, Hematology, Janus Kinase 2, Middle Aged, Prognosis, medicine.disease, Survival Rate, Oncology, Mutation, Female, France, business, Follow-Up Studies, 030215 immunology
Abstract

International audience; No abstract available

Published
2020

7. Should Transplantation Still Be Considered for Ph1-Negative Myeloproliferative Neoplasms in Transformation?

Author

David Michonneau, Gérard Socié, Flore Sicre de Fontbrune, Lionel Ades, Bruno Cassinat, Raphael Itzykson, Mathilde Ruggiu, Emmanuelle Clappier, Jean-Jacques Kiladjian, Marie Robin, Emmanuel Raffoux, Stéphane Giraudier, Régis Peffault de Latour, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Paris (UP), 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 de Paris (UP), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976))

Subjects
medicine.medical_specialty, Allogeneic transplantation, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Hematopoietic stem cell transplantation, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Patient age, Neoplasms, Internal medicine, Overall survival, Humans, Transplantation, Homologous, Medicine, Retrospective Studies, Transplantation, Chemotherapy, Myeloproliferative Disorders, business.industry, Hematopoietic Stem Cell Transplantation, Hematology, 3. Good health, Child, Preschool, 030220 oncology & carcinogenesis, Cohort, business, 030215 immunology
Abstract

BCR-ABL-negative myeloproliferative neoplasms (MPNs) in transformation have a dismal prognosis, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the sole curative therapeutic option. We retrospectively analyzed 53 molecularly annotated patients treated at Saint Louis Hospital, Paris, diagnosed with MPN in transformation between 2008 and 2018. The median patient age was 65 years, and the median interval between MPN diagnosis and MPN transformation was 46 months. The median overall survival (OS) of the entire cohort after transformation was 7.1 months. OS was better for patients treated with hypomethylating agents (HMAs) or with chemotherapy compared than for those treated by best supportive care or single-agent targeted therapy (median, 9.1 months versus 1.5 months; P.001). Patients treated with chemotherapy more often achieved complete remission compared with those treated with HMAs (68% versus 29%; P = .02), and were more often candidates for transplantation (59% versus 14%; P = .02), but the median OS was similar in the 2 groups. We then compared the outcomes in transplant recipients and nonrecipients using the Mantel-Byar methodology and found that allo-HSCT did not improve survival. In multivariate analysis, independent factors in prognosis were performance status at transformation (P.01), initial treatment with HMAs or chemotherapy (P = .02), and the ability to achieve complete remission during follow-up (P.01). Our data demonstrate that the indication for allo-HSCT for high-risk MPN should be discussed before transformation, because transplantation rescues few patients after transformation.

Published
2020

8. MPL mutations in essential thrombocythemia uncover a common path of activation with eltrombopag dependent on W491

Author

Jean-Marc Zini, Serge Carillo, Benjamin Papoular, Stefan N. Constantinescu, Emilie Leroy, Bruno Cassinat, Ilyas Chachoua, Leila N. Varghese, Steven O. Smith, Gabriel Levy, Jean-Philippe Defour, De Duve Institute, Université Catholique de Louvain = Catholic University of Louvain (UCL), Ludwig Institute for Cancer Research, Walloon Excellence in Life sciences and BIOtechnology [Liège] (WELBIO), Cliniques Universitaires Saint-Luc [Bruxelles], Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 de Paris (UP), Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), De Duve Institute, Université Catholique de Louvain, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), UCL - SSS/DDUV/SIGN - Cell signalling, UCL - (SLuc) Service de biologie hématologique, UCL - (SLuc) Service d'hématologie, and UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique

Subjects
Immunology, Mutant, Eltrombopag, Mutagenesis (molecular biology technique), MESH: Receptors, Thrombopoietin / genetics, Signal Transduction / drug effects, Thrombocythemia, Essential / diagnosis, Thrombocythemia, Essential / genetics, Thrombocythemia, Essential / metabolism, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Alleles, Amino Acid Substitution, Benzoates / pharmacology, Cell Line, Genetic Association Studies, Genetic Predisposition to Disease, medicine.disease_cause, Biochemistry, Benzoates, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Protein-fragment complementation assay, medicine, Humans, Alleles, 030304 developmental biology, Thrombopoietin receptor, 0303 health sciences, Mutation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Phenotype, Transmembrane protein, 3. Good health, Cell biology, Hydrazines, chemistry, 030220 oncology & carcinogenesis, Pyrazoles, MESH: Humans, Hydrazines / pharmacology, Pyrazoles / pharmacology, Receptors, Thrombopoietin / agonists, Receptors, Thrombopoietin, Signal Transduction, Thrombocythemia, Essential
Abstract

Mutations in the MPL gene encoding the human thrombopoietin receptor (TpoR) drive sporadic and familial essential thrombocythemias (ETs). We identified 2 ET patients harboring double mutations in cis in MPL, namely, L498W-H499C and H499Y-S505N. Using biochemical and signaling assays along with partial saturation mutagenesis, we showed that L498W is an activating mutation potentiated by H499C and that H499C and H499Y enhance the activity of the canonical S505N mutation. L498W and H499C can activate a truncated TpoR mutant, which lacks the extracellular domain, indicating these mutations act on the transmembrane (TM) cytosolic domain. Using a protein complementation assay, we showed that L498W and H499C strongly drive dimerization of TpoR. Activation by tryptophan substitution is exquisitely specific for position 498. Using structure-guided mutagenesis, we identified upstream amino acid W491 as a key residue required for activation by L498W or canonical activating mutations such as S505N and W515K, as well as by eltrombopag. Structural data point to a common dimerization and activation path for TpoR via its TM domain that is shared between the small-molecule agonist eltrombopag and canonical and novel activating TpoR mutations that all depend on W491, a potentially accessible extracellular residue that could become a target for therapeutic intervention.

Published
2020

9. A Constitutional Activating MET Mutation Makes the Genetic Link between Malignancies and Chronic Inflammatory Diseases

Author

Morad El Bouchtaoui, Marianne Ziol, Guilhem Bousquet, Anne Janin, Irmine Loisel-Ferreira, Bruno Cassinat, Carèle Fedronie, Christophe Leboeuf, Jean-Jacques Kiladjian, Jean-Paul Feugeas, Rachida Ait El Far, Chrystophe Ferreira, Marcio Do Cruzeiro, Géraldine Falgarone, Marc Espié, Cancer et Transplantation : Physiopathologie et Réponse Thérapeutique (UMR 1165), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] (PRHTEC), 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 - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Plateforme ANIMA 5 [UNIV Paris Descartes], Université Paris Descartes - Paris 5 (UPD5)-Cochin-Necker, Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre des maladies du sein [AP-HP Hôpital Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université de Paris 13 - Paris Nord Villetaneuse, Service de Biologie Cellulaire [AP-HP, Hôpital 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), Chu (saint-Louis)/inserm, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Service de Pathologie [AP-HP Hôpital Saint-Louis, Paris], Université Paris Diderot - Paris 7 (UPD7)-Hopital Saint-Louis [AP-HP] (AP-HP), Service d'Oncologie Médicale [AP-HP Hôpital Avicenne], Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie Pathologique [Bondy], Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Université Paris 13 (UP13), Laboratoire de Biologie Cellulaire [AP-HP Hôpital Saint-Louis], Centre d'Investigations Cliniques [AP-HP Hôpital Saint-Louis], Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biologie [Besançon] (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13), Inserm et l'Université Paris 7., Ratajczak, Philippe, Université Paris Diderot - Paris 7 (UPD7)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Université de Paris (UP)-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 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)

Subjects
0301 basic medicine, Cancer Research, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Myeloproliferation, Skin Squamous Cell Carcinoma, Activating MET Mutation, Medicine, Copy-number variation, Thyroid cancer, Mutation, business.industry, Cancer, medicine.disease, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Cancer research, business
Abstract

Purpose: The genesis of all cancers results from an accumulation of mutations, constitutional and/or acquired when induced by external mutagenic factors. High-speed technologies for genome sequencing have completely changed the study of disease genetics, but with limited knowledge of the functional value of most genetic changes. Experimental Design: Here, we proposed an innovative individual approach by studying tissue samples from a young woman with an unusual association of breast cancer, polycythemia vera, and rheumatoid arthritis. We performed genomic analyses for copy number variations and point mutations on laser-microdissected tumor cells from the breast cancer, and on CD34+ cells sorted from bone marrow aspiration, to identify gene abnormalities common to these two types of cell populations. Results: Using ONCOSCAN technology, we identified a constitutional pR988C, c2962C>T mutation of MET. Using CRISPR-Cas9 technology, we established pR988C MET-mutated transgenic mice, which reproduced the autoimmune diseases and myeloproliferation found in our index-case; one of the transgenic mice spontaneously developed a skin squamous cell carcinoma. We also showed that additional mutagenic factors were required to induce cancers, including skin squamous cell carcinoma and thyroid cancer. Using an anti-MET drug, cabozantinib, we demonstrated for the first time the functional role of this mutation in the maintenance of myeloproliferation and rheumatoid arthritis, and in cancer genesis. Conclusions: Our study opens a considerable field of application in the domain of constitutional genetics, to establish genetic links between cancers and other very different severe diseases.

Published
2019

10. Genetic analysis of therapy-related myeloid neoplasms occurring after intensive treatment for acute promyelocytic leukemia

Author

Eric Delabesse, Sandrine Hayette, Lionel Ades, Sophie Park, Virginie Eclache, Bruno Cassinat, Cecile Bally, Aline Renneville, Xavier Thomas, Jean Feuillard, Philippe Attias, Pierre Fenaux, Julie Lejeune, Hassan Farhat, Christine Terré, Claude Preudhomme, Alice Marceau-Renaut, Sylvie Chevret, Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Sciences Po Grenoble - Institut d'études politiques de Grenoble (IEPG), Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'hématologie Hôpital Mignot, Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hématologie -Immunologie -Cibles thérapeutiques, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier de Versailles André Mignot (CHV), Service d'hématologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), CHU Grenoble, Service de biostatistiques et information médicale [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie clinique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Avicenne, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), CHU Versailles, Centre Hospitalier de Versailles (CHV), CHU Necker - Enfants Malades [AP-HP]-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)

Subjects
Acute promyelocytic leukemia, Adult, Cancer Research, Myeloid, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Bioinformatics, Genetic analysis, 03 medical and health sciences, 0302 clinical medicine, Leukemia, Promyelocytic, Acute, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetic variation, Antineoplastic Combined Chemotherapy Protocols, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Humans, Genetic Testing, Allele, Alleles, ComputingMilieux_MISCELLANEOUS, Genetic testing, medicine.diagnostic_test, Radiotherapy, business.industry, Genetic Variation, Neoplasms, Second Primary, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, medicine.disease, 3. Good health, Radiation therapy, medicine.anatomical_structure, Oncology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Mutation, business, Biomarkers, 030215 immunology
Abstract

International audience

Published
2018

11. The role of LNK/SH2B3 genetic alterations in myeloproliferative neoplasms and other hematological disorders

Author

Laura Velazquez, Emmanuelle Verger, J J Kiladjian, Nabih Maslah, Bruno Cassinat, and INSERM U1197

Subjects
0301 basic medicine, Cancer Research, Context (language use), Polycythemia, Gene mutation, Biology, medicine.disease_cause, Germline, 03 medical and health sciences, medicine, Animals, Humans, Epigenetics, Gene, ComputingMilieux_MISCELLANEOUS, Adaptor Proteins, Signal Transducing, Regulation of gene expression, Genetics, Mutation, Myeloproliferative Disorders, Intracellular Signaling Peptides and Proteins, Proteins, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Janus Kinase 2, Hematologic Diseases, Phenotype, 3. Good health, 030104 developmental biology, Oncology, Hematologic Neoplasms
Abstract

Malignant hematological diseases are mainly because of the occurrence of molecular abnormalities leading to the deregulation of signaling pathways essential for precise cell behavior. High-resolution genome analysis using microarray and large-scale sequencing have helped identify several important acquired gene mutations that are responsible for such signaling deregulations across different hematological malignancies. In particular, the genetic landscape of classical myeloproliferative neoplasms (MPNs) has been in large part completed with the identification of driver mutations (targeting the cytokine receptor/Janus-activated kinase 2 (JAK2) pathway) that determine MPN phenotype, as well as additional mutations mainly affecting the regulation of gene expression (epigenetics or splicing regulators) and signaling. At present, most efforts concentrate in understanding how all these genetic alterations intertwine together to influence disease evolution and/or dictate clinical phenotype in order to use them to personalize diagnostic and clinical care. However, it is now evident that factors other than somatic mutations also play an important role in MPN disease initiation and progression, among which germline predisposition (single-nucleotide polymorphisms and haplotypes) may strongly influence the occurrence of MPNs. In this context, the LNK inhibitory adaptor protein encoded by the LNK/SH2B adaptor protein 3 (SH2B3) gene is the target of several genetic variations, acquired or inherited in MPNs, lymphoid leukemia and nonmalignant hematological diseases, underlying its importance in these pathological processes. As LNK adaptor is a key regulator of normal hematopoiesis, understanding the consequences of LNK variants on its protein functions and on driver or other mutations could be helpful to correlate genotype and phenotype of patients and to develop therapeutic strategies to target this molecule. In this review we summarize the current knowledge of LNK function in normal hematopoiesis, the different SH2B3 mutations reported to date and discuss how these genetic variations may influence the development of hematological malignancies.

Published
2017

12. New chimeric RNAs in acute myeloid leukemia

Author

Anne Laure Bougé, Anthony Boureux, Sacha Beaumeunier, Sébastien Riquier, Jean-Baptiste Gaillard, Nicolas Gilbert, Jean-Marc Lemaitre, Nicolas Philippe, Jérôme Audoux, Andre Megarbane, Delphine Bacq-Daian, Ronnie Alves, Christine Chomienne, Thérèse Commes, Florence Ruffle, Elias Bou Samra, Bruno Cassinat, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université Paris-Saclay, Institut Curie [Paris], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hémopathies Myéloïdes : Cellules Souches, Modèles Pré-Cliniques et Recherche Translationnelle (UMR 1131), 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), Institut de Génomique d'Evry (IG), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Philips, Alexandre, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
0301 basic medicine, bioinformatics analysis, chimeric RNA, [SDV]Life Sciences [q-bio], Computational biology, acute myeloid leukemia, Biology, Leukemia & Proliferative Disorders of Hematic Cells, Bioinformatics, DNA sequencing, General Biochemistry, Genetics and Molecular Biology, Exon, 03 medical and health sciences, 0302 clinical medicine, Chimeric RNA, medicine, splice, Classification (CRAC), PML-RARA, General Pharmacology, Toxicology and Pharmaceutics, Gene, ComputingMilieux_MISCELLANEOUS, General Immunology and Microbiology, TRIM28, biomarkers, Myeloid leukemia, Articles, General Medicine, RNAseq, medicine.disease, Complex Read Analysis, 3. Good health, [SDV] Life Sciences [q-bio], Leukemia, 030104 developmental biology, RNA editing, 030220 oncology & carcinogenesis, Research Article
Abstract

Background: High-throughput next generation sequencing (NGS) technologies enable the detection of biomarkers used for tumor classification, disease monitoring and cancer therapy. Whole-transcriptome analysis using RNA-seq is important, not only as a means of understanding the mechanisms responsible for complex diseases but also to efficiently identify novel genes/exons, splice isoforms, RNA editing, allele-specific mutations, differential gene expression and fusion-transcripts or chimeric RNA (chRNA). Methods: We used Crac, a tool that uses genomic locations and local coverage to classify biological events and directly infer splice and chimeric junctions within a single read. Crac’s algorithm extracts transcriptional chimeric events irrespective of annotation with a high sensitivity, and CracTools was used to aggregate, annotate and filter the chRNA reads. The selected chRNA candidates were validated by real time PCR and sequencing. In order to check the tumor specific expression of chRNA, we analyzed a publicly available dataset using a new tag search approach. Results: We present data related to acute myeloid leukemia (AML) RNA-seq analysis. We highlight novel biological cases of chRNA, in addition to previously well characterized leukemia chRNA. We have identified and validated 17 chRNAs among 3 AML patients: 10 from an AML patient with a translocation between chromosomes 15 and 17 (AML-t(15;17), 4 from patient with normal karyotype (AML-NK) 3 from a patient with chromosomal 16 inversion (AML-inv16). The new fusion transcripts can be classified into four groups according to the exon organization. Conclusions: All groups suggest complex but distinct synthesis mechanisms involving either collinear exons of different genes, non-collinear exons, or exons of different chromosomes. Finally, we check tumor-specific expression in a larger RNA-seq AML cohort and identify new AML biomarkers that could improve diagnosis and prognosis of AML.

Published
2017

13. Quantification of the Mutant CALR Allelic Burden by Digital PCR

Author

Arnaud Saint-Lézer, Marie Robin, Eric Lippert, Emmanuelle Verger, Marina Migeon, Bruno Cassinat, Francois-Xavier Mahon, Gérard Socié, Audrey Bidet, Chloé James, Olivier Mansier, Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, and Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Oncology, medicine.medical_specialty, medicine.medical_treatment, Hematopoietic stem cell transplantation, Pathology and Forensic Medicine, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Internal medicine, medicine, Article CLINIQUE, Neoplasm, Digital polymerase chain reaction, Myelofibrosis, Polymerase chain reaction, Myeloproliferative neoplasm, Genetics, biology, business.industry, Article RECHERCHE, medicine.disease, Minimal residual disease, 3. Good health, 030220 oncology & carcinogenesis, biology.protein, Molecular Medicine, business, Calreticulin, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract

With the recent discovery of CALR mutations, >80% of patients with myeloproliferative neoplasms carry a phenotype-driving mutation. For JAK2 V617F, the most frequent mutation in myeloproliferative neoplasms, accurate determination of mutational loads is of interest at diagnosis, for phenotypic and prognostic purposes, and during follow-up for minimal residual disease assessment. We developed a digital PCR technique that allowed the accurate determination of CALR allelic burdens for the main mutations (types 1 and 2). Compared with the commonly used fluorescent PCR product analysis, digital PCR is more precise, reproducible, and accurate. Furthermore, this method reached a very high sensitivity. We detected at least 0.025% CALR mutants. It can thus be used for patient characterization at diagnosis and for minimal residual disease monitoring. When applied to patients with primary myelofibrosis who underwent hematopoietic stem cell transplant, the digital PCR detected low levels of minimal residual disease. After negativation of the mutational load in all patients, the disease reappeared at a low level in one patient, preceding hematologic relapse. In conclusion, digital PCR adapted to type 1 and 2 CALR mutations is an inexpensive, highly precise, and sensitive technique suitable for evaluation of myeloproliferative neoplasm patients during follow-up.

Published
2016

14. Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network

Author

Mohammad Reza Ahmadian, Dieter Häussinger, Brigitte Nelken, Francoise Mechinaud, Marion Strullu, André Baruchel, Steven Gazal, Marilyne Poirée, Nicolas Sirvent, Jocelyne Vivent, Catherine Paillard, Radovan Dvorsky, Sabrina Pereira, Capucine Picard, Jean-Hugues Dalle, Emmanuelle Verger, Odile Fenneteau, Bruno Cassinat, Hélène Cavé, Yves Reguerre, Saeideh Nakhaei-Rad, Elodie Lainey, Aurélie Caye, Yves Bertrand, Fabien Guidez, Audrey Contet, Arnaud Petit, Kazem Nouri, Dominique Vidaud, Claire Galambrun, Julie Lachenaud, Christine Chomienne, Dalila Adjaoud, Hémopathies Myéloïdes : Cellules Souches, Modèles Pré-Cliniques et Recherche Translationnelle (UMR 1131), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Institute of Biochemistry & Molecular Biology II, Heinrich Heine University Medical Center, Fédération de Génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux (EA 7331), Université Paris Descartes - Paris 5 (UPD5), Service de biochimie et de génétique moléculaire [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Assistance Publique - Hôpitaux de Marseille (APHM), CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-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), Service d'Hématologie et d'Oncologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital l'Archet, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire [Grenoble] (CHU), Hôpital de Hautepierre [Strasbourg], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], 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 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Heinrich-Heine-Universität Düsseldorf [Düsseldorf], and Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
Male, DNA Copy Number Variations, Somatic cell, Biology, medicine.disease_cause, Methylation, Germline, Histones, Phosphatidylinositol 3-Kinases, Genetics, medicine, Humans, Gene Regulatory Networks, Child, PI3K/AKT/mTOR pathway, Myeloproliferative neoplasm, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Microscopy, Confocal, Juvenile myelomonocytic leukemia, Polycomb Repressive Complex 2, Infant, Myeloid leukemia, Acetylation, Sequence Analysis, DNA, medicine.disease, Survival Analysis, 3. Good health, Protein Subunits, Leukemia, Leukemia, Myelomonocytic, Juvenile, Leukemia, Myeloid, Child, Preschool, Acute Disease, Disease Progression, ras Proteins, Cancer research, Female, Transcriptome, Signal Transduction
Abstract

International audience; Juvenile myelomonocytic leukemia (JMML) is a rare and severe myelodysplastic and myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations. Genetic profiling and whole-exome sequencing of a large JMML cohort (118 and 30 cases, respectively) uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38 events/Mb/case) and restricted to sporadic (49/78; 63%) or neurofibromatosis type 1 (NF1)-associated (8/8; 100%) JMML cases. Multiple concomitant genetic hits targeting the RAS pathway were identified in 13 of 78 cases (17%), disproving the concept of mutually exclusive RAS pathway mutations and defining new pathways activated in JMML involving phosphoinositide 3-kinase (PI3K) and the mTORC2 complex through RAC2 mutation. Furthermore, this study highlights PRC2 loss (26/78; 33% of sporadic JMML cases) that switches the methylation/acetylation status of lysine 27 of histone H3 in JMML cases with altered RAS and PRC2 pathways. Finally, the association between JMML outcome and mutational profile suggests a dose-dependent effect for RAS pathway activation, distinguishing very aggressive JMML rapidly progressing to acute myeloid leukemia.

Published
2015

15. Association of a single-nucleotide polymorphism in the SH2B3 gene with JAK2V617F-positive myeloproliferative neoplasms

Author

Stéphane Giraudier, Elodie Lesteven, Nadine Varin-Blank, Carole Tonetti, Laura Velazquez, Marie Picque, Jean-Jacques Kiladjian, Fanny Baran-Marszak, Bruno Cassinat, and INSERM U1197

Subjects
Genetics, Mutation, medicine.medical_treatment, Immunology, Myeloproliferative disease, Single-nucleotide polymorphism, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, Biology, medicine.disease_cause, Biochemistry, Cytokine, hemic and lymphatic diseases, medicine, SH2B3 Gene, Receptor, Gene, Lymphocyte Adaptor Protein, ComputingMilieux_MISCELLANEOUS
Abstract

To the editor: In a recent paper, Perez-Garcia et al described an inherited mutation in the SH2B3 gene associated with the development of acute lymphoblastic leukemia.[1][1] SH2B3 encodes the lymphocyte adaptor protein (LNK) that negatively modulates the signaling of several cytokine receptors

Published
2014

16. Retrospective study of allogeneic haematopoietic stem-cell transplantation for myelofibrosis

Author

Jérôme Cornillon, A. Cabrespine, J.-O. Bay, Bruno Cassinat, R. Peffault de Latour, Raphaël Porcher, Severine Lissandre, J.Y. Cahn, V. Cacheux, Gérard Socié, Marie Robin, TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Institut Mondor de Recherche Biomédicale (IMRB), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10

Subjects
Transplantation Conditioning, Graft vs Host Disease, Gastroenterology, 0302 clinical medicine, hemic and lymphatic diseases, Medicine, MESH: Transplantation Conditioning, MESH: Aged, Hematology, Leukemia, MESH: Middle Aged, Hematopoietic Stem Cell Transplantation, Middle Aged, 3. Good health, Fludarabine, Haematopoiesis, surgical procedures, operative, MESH: Young Adult, 030220 oncology & carcinogenesis, MESH: Survival Analysis, MESH: Primary Myelofibrosis, medicine.drug, Adult, medicine.medical_specialty, Adolescent, MESH: Graft vs Host Disease, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Young Adult, Internal medicine, MESH: Leukemia, MESH: Transplantation, Homologous, Humans, Transplantation, Homologous, Myelofibrosis, Survival analysis, MESH: Hematopoietic Stem Cell Transplantation, Aged, Retrospective Studies, MESH: Adolescent, Transplantation, MESH: Humans, business.industry, Retrospective cohort study, MESH: Adult, MESH: Retrospective Studies, medicine.disease, Survival Analysis, Surgery, Graft-versus-host disease, Primary Myelofibrosis, business, 030215 immunology
Abstract

International audience; Allogeneic haematopoietic stem-cell transplantation (HSCT) is the only curative treatment for myelofibrosis. We retrospectively analyzed the outcome of patients who underwent allogeneic HSCT, 1994-2008, and the potential risk factors affecting non-relapse mortality (NRM), OS and relapse-free survival (RFS). A total of 39 patients, 15-65 (median 49) years old, diagnosed with primary (n=27) or secondary (n=12) myelofibrosis underwent HSCT (25 related and 14 unrelated). In ten patients, disease had transformed into acute leukaemia. Lille prognosis score was low for 9, intermediate for 16 and high for 14 patients. The conditioning regimen was myeloablative (MAC) for 15 and reduced-intensity (RIC) fludarabine-based for 24, with successful engraftment in 38 patients. A total of 31 patients developed grade I-IV GvHD; 19 developed chronic GvHD. The 3-year OS, RFS and NRM rates (95% confidence interval) were 60% (42-74), 54% (37-59) and 30% (30-45), respectively.

Published
2011

17. Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukemia (JMML)

Author

O Fenneteau, J Derain-Court, N Royer, Bruno Cassinat, C Désirée, Francoise Mechinaud, Claire Galambrun, B. Perez, Nicole Philip, M L Menot, Sophie Kaltenbach, Sabrina Pereira, André Baruchel, Alexandra Salmon, N Ben Romdhane, Christine Chomienne, Bertrand Isidor, Julie Lachenaud, Hélène Cavé, Alain Verloes, Hématologie -Immunologie -Cibles thérapeutiques, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Service d'Oncologie Hématologie Pédiatrique, Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Hématologie pédiatrique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'Hématologie, Hôpital La Rabta [Tunis], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Génétique, Service de biochimie-hormonologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie et immunologie pédiatrique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), and Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
Male, medicine.medical_specialty, Microcephaly, Developmental Disabilities, Biology, Germline, Loss of heterozygosity, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Molecular genetics, hemic and lymphatic diseases, Genetics, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Proto-Oncogene Proteins c-cbl, Child, Genetics (clinical), Germ-Line Mutation, Growth Disorders, 030304 developmental biology, Paediatric oncology, 0303 health sciences, Haematology (incl Blood transfusion), Monocyte proliferation, Syndrome, medicine.disease, 3. Good health, Leukemia, Myelomonocytic, Juvenile, 030220 oncology & carcinogenesis, Child, Preschool, Chromosomal region, Female
Abstract

Background CBL missense mutations have recently been associated with juvenile myelomonocytic leukaemia (JMML), an aggressive myeloproliferative and myelodysplastic neoplasm of early childhood characterised by excessive macrophage/monocyte proliferation. CBL, an E3 ubiquitin ligase and a multi-adaptor protein, controls proliferative signalling networks by downregulating the growth factor receptor signalling cascades in various cell types. Methods and results CBL mutations were screened in 65 patients with JMML. A homozygous mutation of CBL was found in leukaemic cells of 4/65 (6%) patients. In all cases, copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus, was demonstrated. Three of these four patients displayed additional features suggestive of an underlying developmental condition. A heterozygous germline CBL p.Y371H substitution was found in each of them and was inherited from the father in one patient. The germline mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells. The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a ‘CBL syndrome’ to be tentatively delineated. Learning difficulties and postnatal growth retardation may be part of the phenotype. Conclusion A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.

Published
2010

18. Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity

Author

Thérèse Commes, Laurent Manchon, Bruno Cassinat, Christine Chomienne, Aurelie Baudet, Ronan Quere, Jacques Marti, David Piquemal, Gerald Bertrand, 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), Hématologie -Immunologie -Cibles thérapeutiques, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Skuldtech. Cap Delta - ZAC Euromedecine II. 1682, rue de la Valsière, Hémopathies Myéloïdes : Cellules Souches, Modèles Pré-Cliniques et Recherche Translationnelle (UMR 1131), 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), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Transcription, Genetic, [SDV]Life Sciences [q-bio], Retinoic acid, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Cytochrome P-450 Enzyme System, Leukemia, Promyelocytic, Acute, Tumor Cells, Cultured, Retinoid, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Gene Expression Regulation, Leukemic, Hematology, Retinoic Acid 4-Hydroxylase, 3. Good health, 030220 oncology & carcinogenesis, Disease Progression, medicine.drug, Acute promyelocytic leukemia, medicine.drug_class, Immunology, Tretinoin, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Models, Biological, 03 medical and health sciences, CYP26A1, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Enhancer, Transcription factor, 030304 developmental biology, Cell Proliferation, Gene Library, Homeodomain Proteins, [SDV.GEN]Life Sciences [q-bio]/Genetics, Dose-Response Relationship, Drug, Gene Expression Profiling, Interleukin-8, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, medicine.disease, Retinoic acid receptor, Homeobox A10 Proteins, chemistry, Drug Resistance, Neoplasm, Pharmacogenetics, Cancer research
Abstract

Disease relapse sometimes occurs after acute promyelocytic leukemia (APL) therapy with all-trans retinoic acid (ATRA). Among the diagnostic parameters predicting relapse, heterogeneity in the in vitro differentiation rate of blasts is an independent factor. To identify biologic networks involved in resistance, we conducted pharmacogenomic studies in APL blasts displaying distinct ATRA sensitivities. Although the expression profiles of genes invested in differentiation were similarly modulated in low- and high-sensitive blasts, low-sensitive cells showed higher levels of transcription of ATRA-target genes, transcriptional regulators, chromatin remodelers, and transcription factors. In opposition, only high-sensitive blasts expressed the CYP26A1 gene, encoding the p450 cytochrome which is known to be involved in retinoic acid catabolism. In NB4 cells, ATRA treatment activates a novel signaling pathway, whereby interleukin-8 stimulates the expression of the homeobox transcription factor HOXA10v2, an effective enhancer of CYP26A1 transcription. These data were corroborated in primary APL cells, as maturation levels correlated with CYP26A1 expression. Treatment with a retinoic acid metabolism blocking agent (RAMBA) results in high-nucleoplasmic concentrations of retinoid and growth of NB4-resistant subclones. Hence, for APL blasts associated with poor prognosis, the low CYP26A1 expression may explain high risk of resistance installation, by increased retinoid pressure. Pharmacogenomic profiles of genes involved in retinoid acid metabolism may help to optimize anticancer therapies, including retinoids.

Published
2007

19. Mechanisms of clonal selection in myeloproliferative neoplasms (JAK2V617F) subclonal selection and transformation after TP53 inactivation

Author

Gou, Panhong, 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), Université Paris Cité, Stéphane Giraudier, Bruno Cassinat, and STAR, ABES

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Cellule souche hématopoïétique, Knock-in ouse model, Modèle de souris knock-in, Hématopoïèse, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, TP53, JAK2V617F, Néoplasies myéloprolifératives, Hematopoietic stem cell, Myeloproliferative neoplasms, Hematopoiesis
Abstract

Hematopoiesis is the production of all of the cellular components of blood. It occurs within the hematopoietic system, including organs and tissues such as the bone marrow, liver, and spleen. It begins early in the development of an embryo, well before birth, and continues all the life of an individual. During adult life, hematopoiesis occurs in the marrow of the long bones like femur and tibia, but mainly in the pelvis, cranium, vertebrae, and sternum. Hematopoiesis represents approximately 5% of total body mass in human healthy adult, 3% of total body mass in rat and 2% in dogs. In pathological conditions, the lymph nodes, liver, and spleen may regain their hematopoietic function that is called extramedullary hematopoiesis (EMH). Pathological hematopoiesis may show alterations in the number and morphology of different cell lineages in peripheral blood and mono- or multilineage cell changes in the bone marrow. Both normal and pathological hematopoiesis can be divided into two different systems, myeloid and lymphoid, according to the different lineages. Myeloid neoplasms include acute myeloid leukemia (AML) and related aggressive myeloid neoplasms, myeloproliferative neoplasms (MPN), mastocytosis, myelodysplastic syndromes (MDS), and MDS/MPN syndromes. JAK2V617F is one of the most common mutations expressed in myeloid neoplasms and more particularly in MPN where this mutation has been demonstrated as causative of the disorders. However, other genes can be abnormal in myeloid neoplasms. TP53 which encodes the tumor suppressor P53 is the most frequently mutated gene in cancers. Surprisingly, it is not one of the most mutated genes in myeloid neoplasms, however it has been suggested that TP53 could be associated to the evolution of MPN and MDS to acute leukemias. The aim of this work was first to better understand the clonal advantage of JAK2V617F mutated cells based on the hypothesis that instead of steady state JAK2V617F hematopoiesis the clonal advantage may be due to stressed JAK2V617F stem cells, and second to better delineate what is TP53 dependent or independent in MPN and verify if the TP53 inactivation can transform the MPN into AML., L'hématopoïèse est la production de tous les composants cellulaires du sang. Il se produit dans le système hématopoïétique, y compris les organes et les tissus tels que la moelle osseuse, le foie et la rate. Il commence tôt dans le développement d'un embryon, bien avant la naissance, et se poursuit toute la vie d'un individu. Au cours de la vie adulte, l'hématopoïèse se produit dans la moelle des os longs comme le fémur et le tibia, mais principalement dans le bassin, le crâne, les vertèbres et le sternum. L'hématopoïèse représente environ 5% de la masse corporelle totale chez l'homme adulte en bonne santé, 3% de la masse corporelle totale chez le rat et 2% chez le chien. Dans des conditions pathologiques, les ganglions lymphatiques, le foie et la rate peuvent retrouver leur fonction hématopoïétique appelée hématopoïèse extramédullaire (HEM). L'hématopoïèse pathologique peut montrer des altérations du nombre et de la morphologie des différentes lignées cellulaires dans le sang périphérique et des modifications cellulaires mono- ou multilignées dans la moelle osseuse. L'hématopoïèse normale et pathologique peut être divisée en deux systèmes différents, myéloïde et lymphoïde, selon les différentes lignées. Les néoplasmes myéloïdes comprennent la leucémie myéloïde aiguë (LMA) et les néoplasmes myéloïdes agressifs associés, les néoplasmes myéloprolifératifs (NPP), la mastocytose, les syndromes myélodysplasiques (SMD) et les syndromes MDS / MPN. JAK2V617F est l'une des mutations les plus courantes exprimées dans les néoplasmes myéloïdes et plus particulièrement dans le MPN où cette mutation a été démontrée comme causale des troubles. Cependant, d'autres gènes peuvent être anormaux dans les néoplasmes myéloïdes. TP53 qui code pour le suppresseur de tumeur P53 est le gène le plus fréquemment muté dans les cancers. Étonnamment, ce n'est pas l'un des gènes les plus mutés dans les néoplasmes myéloïdes, mais il a été suggéré que TP53 pourrait être associé à l'évolution du MPN et du SMD en leucémies aiguës. Le but de ce travail était d'abord de mieux comprendre l'avantage clonal des cellules mutées JAK2V617F en partant de l'hypothèse qu'au lieu de l'hématopoïèse de JAK2V617F à l'état d'équilibre, l'avantage clonal peut être dû à des cellules souches JAK2V617F stressées, et deuxièmement de mieux délimiter ce qui dépend de TP53 ou indépendant en MPN et vérifiez si l'inactivation du TP53 peut transformer le MPN en AML.

Published
2021

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