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2. The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11

Author

Virginie Eclache, John Boudjarane, Naïs Prade, Stéphanie Struski, Laetitia Largeaud, Cyril Broccardo, Joop H. Jansen, Christine Terré, Marie-Agnès Collonge-Rame, Pierre-Yves Juvin, Dominique Penther, Stéphanie Lagarde, Antoine Ittel, Véronique Mansat-De Mas, G Ameye, Isabelle Luquet, Marina Lafage-Pochitaloff, Carole Barin, David Rombaut, Bastien Gerby, Carine Gervais, Steven Richebourg, Oliver M. Dovey, Pierre Bories, Christine Lefebvre, Isabelle Radford-Weiss, Audrey Bidet, Isabelle Tigaud, George S. Vassiliou, Benedicte Ribourtout, Tobias Tekath, Michaela Fontenay, Lucienne Michaux, Sylvie Hébrard, Hélène Antoine-Poirel, Laura Jamrog, Vincent Fregona, Nathalie Nadal, Eric Delabesse, Véronique Baccini, Kosuke Yusa, Gerby, Bastien [0000-0002-2657-4200], Baccini, Véronique [0000-0003-3913-7664], Largeaud, Laetitia [0000-0001-5341-5427], Fregona, Vincent [0000-0003-4857-1737], Prade, Naïs [0000-0003-4718-7848], Jamrog, Laura [0000-0003-2288-0806], Mansat-De Mas, Véronique [0000-0003-1878-9129], Dovey, Oliver M [0000-0003-3586-4813], Yusa, Kosuke [0000-0002-3442-021X], Vassiliou, George S [0000-0003-4337-8022], Jansen, Joop H [0000-0001-9459-568X], Tekath, Tobias [0000-0002-9315-5452], Rombaut, David [0000-0001-8910-0945], Ameye, Geneviève [0000-0002-5838-2879], Ittel, Antoine [0000-0001-5067-575X], Michaux, Lucienne [0000-0002-8357-7942], Poirel, Hélène A [0000-0002-0712-5127], Struski, Stéphanie [0000-0002-2282-4364], Fontenay, Michaela [0000-0002-5492-6349], Broccardo, Cyril [0000-0003-3016-6549], Delabesse, Eric [0000-0002-0928-0753], Apollo - University of Cambridge Repository, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
INVOLVEMENT, Candidate gene, Myeloid, Tumor suppressor gene, SCORING SYSTEM, [SDV]Life Sciences [q-bio], Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Biology, CLASSIFICATION, 03 medical and health sciences, Mice, 0302 clinical medicine, hemic and lymphatic diseases, medicine, Animals, Humans, Genes, Tumor Suppressor, TSLC1/IGSF4, 030304 developmental biology, MYELODYSPLASTIC SYNDROME, 0303 health sciences, Science & Technology, Myeloid Neoplasia, Myelodysplastic syndromes, MALE-INFERTILITY, Chromosomes, Human, Pair 11, TSLC1, Cell Adhesion Molecule-1, Myeloid leukemia, KARYOTYPE, Hematology, medicine.disease, 3. Good health, Transplantation, Leukemia, Myeloid, Acute, medicine.anatomical_structure, KMT2A, 030220 oncology & carcinogenesis, CELL-ADHESION MOLECULE, Myelodysplastic Syndromes, Cancer research, biology.protein, Female, Bone marrow, Chromosome Deletion, Life Sciences & Biomedicine, LEUKEMIA
Abstract

Key Points We detail at clinical, cytological, cytogenetic, and molecular levels 113 cases of MDS and MDS/MPN with del(11q), a rare recurrent event.CADM1, a tumor suppressor gene identified initially in solid tumors, ATM, CBL, and KMT2A are deleted and/or mutated in del(11q)., Visual Abstract, Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic, and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count, and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A, and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as Tumor Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid-to-myeloid ratio in bone marrow, although not altering their multilineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM, and CBL and mutations of ASXL1, SF3B1, and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies.

Published
2022

3. 3084 – CELL QUIESCENCE AND REPROGRAMMING ARE DISTINCTIVE FEATURES OF PRE-LEUKEMIC STEM CELLS IN B-ACUTE LYMPHOBLASTIC LEUKEMIA

Author

Vincent Fregona, Manon Bayet, Mathieu bouttier, Laetitia Largeaud, Camille Hamelle, Laura Jamrog, Naïs Prade, Stéphanie Lagarde, Sylvie Hebard, Marlène Pasquet, Christine Didier, Ahmed Khamlichi, Cyril Broccardo, Eric Delabesse, Stéphane Mancini, and bastien Gerby

Subjects
Cancer Research, Genetics, Cell Biology, Hematology, Molecular Biology
Published
2022

4. Germline PAX5 mutation predisposes to familial B-cell precursor acute lymphoblastic leukemia

Author

Eric Delabesse, Vincent Fregona, Céline Villenet, Catherine Roche-Lestienne, Céline Berthon, Stephanie Dufrechou, José Fernandes, Nathalie Helevaut, Brigitte Nelken, Sylvie Hébrard, Naïs Prade, Bastien Gerby, Stéphanie Poulain, Laura Jamrog, Claude Preudhomme, Nicolas Duployez, Cyril Broccardo, Aurélie Caillault, Laetitia Largeaud, Martin Figeac, Sophie Lejeune, Alice Marceau-Renaut, Sandrine Geffroy, Camille Hamelle, Laurène Fenwarth, CHU 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), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Toulouse [Toulouse], Hôpital Claude Huriez [Lille], Centre hospitalier [Valenciennes, Nord], Université de Lille, Gerby, Bastien, Université de Lille-UNICANCER, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0303 health sciences, Lymphoblastic Leukemia, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Biology, Hematology, Biology, medicine.disease, Biochemistry, Germline, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, [SDV.CAN] Life Sciences [q-bio]/Cancer, 030220 oncology & carcinogenesis, Acute lymphocytic leukemia, Mutation (genetic algorithm), medicine, Cancer research, PAX5, B cell, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience; No abstract available

Published
2021

5. New Approach to Decipher GATA2 Deficiency Syndrome: Focus on the Recurrent GATA2 R396Q Mutation

Author

Esmaa Sellam, Vincent Fregona, Cyril Broccardo, Naïs Prade, Laetitia Largeaud, Camille Hamelle, Stephanie Dufrechou, Manon Bayet, Christine Didier, Eric Delabesse, Sylvie Hébrard, Marlène Pasquet, Laura Jamrog, and Bastien Gerby

Subjects
Genetics, Focus (computing), GATA2 Deficiency, Immunology, GATA2, Mutation (genetic algorithm), DECIPHER, Cell Biology, Hematology, Biology, Biochemistry
Abstract

Germline GATA2 mutations are identified in a complex disorder termed GATA2 deficiency syndrome. Clinical heterogeneous manifestations are associated with a wide diversity of molecular alterations (missense, frameshift, nonsense, intronic or splicing mutations). Truncating mutations decrease GATA2 expression suggesting a haploinsufficiency mechanism while molecular consequences of missense mutations are ill-known. We focus our research on the most recurrent GATA2 mutation, GATA2 R396Q. Our in vitro results indicate that the ectopic expression of GATA2 R396Q has a strong impact on the clonogenicity associated with an excessive granulocyte differentiation. This data motivates the elaboration of a more physiological approach through the development of a new knock-in mouse model with endogenous expression of Gata2 R396Q mutation. This model allowed us to address the question of the impact of this missense mutation on hematopoiesis at steady state and in challenging conditions. The Gata2R396Q/+ mice showed an abnormal distribution of the immature progenitors Lin - Sca-1 + Kit + (LSK) subpopulations, mainly defines by an increase of the number of aberrant Long-Term Hematopoietic Stem cells (LT-HSC) contrasting with the decrease of LT-HSC population in Gata2+/- mouse model. Functional assays on Gata2R396Q/+ LSK cells revealed also qualitative defects. Indeed, their reconstitution capacity and their response to inflammatory or chemotherapy stimuli seemed to be largely affected. To address at the molecular level the impact of the missense mutation in these progenitors, we combined gene expression analysis with chromatin gene accessibility. These analyses revealed a strong disruption of the cells' ability to respond to stimuli, such as IFN or TNFα signaling, confirming what we observed at the cellular level in functional assays. Furthermore, specific RNA sequencing of the LT-HSC, ST-HSC and MPP3-4 subpopulations showed that the majority of these molecular perturbations are detected in every subpopulation of the LSK cells. In addition, we are able to establish a precise genetic signature in LT-HSC that may be related to their major functional defects. Combination of in vitro and in vivo approaches leads to improve our understanding of GATA2 deficiency syndrome. Modelization of the most recurrent germline Gata2 mutation revealed a different phenotype than the haploinsufficient mouse model. Furthermore, expression of Gata2 R396Q mutation qualitatively impacts the LSK compartment mimicking functional and molecular defects observed in the GATA2 deficiency patients. Disclosures Delabesse: Novartis: Consultancy; Astellas: Consultancy. Pasquet: Novartis: Consultancy.

Published
2021

6. PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice

Author

Guillaume Chemin, Sylvie Hébrard, Chloé Oudinet, Ngoc Sa Nguyen Huu, Pierre Brousset, Stéphanie Lagarde, Laura Jamrog, Vincent Fregona, Cyril Broccardo, Bastien Gerby, Cathy Quelen, Eric Delabesse, Marina Bousquet, Stéphane J. C. Mancini, Naïs Prade, Nelly Rouquié, Charlotte Cresson, Marlène Pasquet, Lucie Coster, Ahmed Amine Khamlichi, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Hématologie pédiatrique, CHU Toulouse [Toulouse], Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), LIttoral ENvironnement et Sociétés - UMR 7266 (LIENSs), Université de La Rochelle (ULR)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), and Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Tumor suppressor gene, Oncogene Proteins, Fusion, Transgene, [SDV]Life Sciences [q-bio], Chromosomal translocation, Mice, Transgenic, Protein Tyrosine Phosphatase, Non-Receptor Type 11, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, medicine, Animals, Gene Knock-In Techniques, Gene, ComputingMilieux_MISCELLANEOUS, B-Lymphocytes, Multidisciplinary, Cell growth, Gene Expression Regulation, Leukemic, PAX5 Transcription Factor, Janus Kinase 3, Neoplasms, Experimental, Biological Sciences, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Fusion protein, Elastin, Leukemia, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Cancer research, PAX5
Abstract

International audience; PAX5 is a well-known haploinsufficient tumor suppressor gene in human B-cell precursor acute lymphoblastic leukemia (B-ALL) and is involved in various chromosomal translocations that fuse a part of PAX5 with other partners. However, the role of PAX5 fusion proteins in BALL initiation and transformation is ill-known. We previously reported a new recurrent t(7;9)(q11;p13) chromosomal translocation in human BALL that juxtaposed PAX5 to the coding sequence of elastin (ELN). To study the function of the resulting PAX5-ELN fusion protein in BALL development, we generated a knockin mouse model in which the PAX5-ELN transgene is expressed specifically in B cells. PAX5-ELN-expressing mice efficiently developed BALL with an incidence of 80%. Leukemic transformation was associated with recurrent secondary mutations on Ptpn11, Kras, Pax5, and Jak3 genes affecting key signaling pathways required for cell proliferation. Our functional studies demonstrate that PAX5-ELN affected B-cell development in vitro and in vivo featuring an aberrant expansion of the pro-B cell compartment at the preleukemic stage. Finally, our molecular and computational approaches identified PAX5-ELN-regulated gene candidates that establish the molecular bases of the pre-leukemic state to drive BALL initiation. Hence, our study provides a new in vivo model of human BALL and strongly implicates PAX5 fusion proteins as potent oncoproteins in leukemia development.

Published
2018

7. PAX5A and PAX5B isoforms are both efficient to drive B cell differentiation

Author

Bastien Gerby, Stéphane J. C. Mancini, Marine Dubois, Laurent Delpy, Michel Cogné, Cyril Broccardo, Laura Jamrog, Naïs Prade, Nelly Rouquié, Charlotte Cresson, Sylvie Hébrard, Stéphanie Lagarde, Eric Delabesse, Sophie Péron, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Hématologie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], 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), Centre de Recherches en Cancérologie de Toulouse (CRCT), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Gerby, Bastien, 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), 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), and Université de Limoges (UNILIM)-Université de Limoges (UNILIM)

Subjects
0301 basic medicine, Gene isoform, [SDV.CAN]Life Sciences [q-bio]/Cancer, acute lymphoblastic leukemia, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, 03 medical and health sciences, Exon, [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], B cell development, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Gene, Transcription factor, B cell, transcription factor, ComputingMilieux_MISCELLANEOUS, Pax5, B cells, Promoter, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Oncology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, PAX5, Ex vivo, Research Paper
Abstract

International audience; Pax5 is the guardian of the B cell identity since it primes or enhances the expression of B cell specific genes and concomitantly represses the expression of B cell inappropriate genes. The tight regulation of Pax5 is therefore required for an efficient B cell differentiation. A defect in its dosage can translate into immunodeficiency or malignant disorders such as leukemia or lymphoma. Pax5 is expressed from two different promoters encoding two isoforms that only differ in the sequence of their first alternative exon. Very little is known regarding the role of the two isoforms during B cell differentiation and the regulation of their expression. Our work aims to characterize the mechanisms of regulation of the expression balance of these two isoforms and their implication in the B cell differentiation process using murine ex vivo analyses. We show that these two isoforms are differentially regulated but have equivalent function during early B cell differentiation and may have functional differences after B cell activation. The tight control of their expression may thus reflect a way to finely tune Pax5 dosage during B cell differentiation process.

Published
2018

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