Academic Journal
Stepwise GATA1 and SMC3 mutations alter megakaryocyte differentiation in a Down syndrome leukemia model
| العنوان: | Stepwise GATA1 and SMC3 mutations alter megakaryocyte differentiation in a Down syndrome leukemia model |
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| المؤلفون: | Arkoun, Brahim, Robert, Elie, Boudia, Fabien, Mazzi, Stefania, Dufour, Virginie, Siret, Aurélie, Mammasse, Yasmine, Aid, Zakia, Vieira, Matthieu, Imanci, Aygun, Aglave, Marine, Cambot, Marie, Petermann, Rachel, Souquere, Sylvie, Rameau, Philippe, Catelain, Cyril, Diot, Romain, Tachdjian, Gérard, Hermine, Olivier, Droin, Nathalie, Debili, Najet, Plo, Isabelle, Malinge, Sébastien, Soler, Eric, Raslova, Hana, Mercher, Thomas, Vainchenker, William |
| المساهمون: | Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo - U1287 Inserm), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut National de la Transfusion Sanguine Paris (INTS), Institut Gustave Roussy (IGR), 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), AP-HP - Hôpital Antoine Béclère Clamart, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques = Molecular mechanisms of hematological disorders and therapeutic implications (ERL 8254), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), The University of Western Australia (UWA), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM) |
| المصدر: | ISSN: 1558-8238 ; The Journal of clinical investigation ; https://hal.science/hal-04441606 ; The Journal of clinical investigation, 2022, 132 (14), pp.131-136. ⟨10.1172/JCI156290⟩. |
| بيانات النشر: | HAL CCSD American Society for Clinical Investigation |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology |
| الوصف: | International audience ; Acute megakaryoblastic leukemia of Down syndrome (DS-AMKL) is a model of clonal evolution from a preleukemic transient myeloproliferative disorder requiring both a trisomy 21 (T21) and a GATA1s mutation to a leukemia driven by additional driver mutations. We modeled the megakaryocyte differentiation defect through stepwise gene editing of GATA1s, SMC3+/–, and MPLW515K, providing 20 different T21 or disomy 21 (D21) induced pluripotent stem cell (iPSC) clones. GATA1s profoundly reshaped iPSC-derived hematopoietic architecture with gradual myeloid-to-megakaryocyte shift and megakaryocyte differentiation alteration upon addition of SMC3 and MPL mutations. Transcriptional, chromatin accessibility, and GATA1-binding data showed alteration of essential megakaryocyte differentiation genes, including NFE2 downregulation that was associated with loss of GATA1s binding and functionally involved in megakaryocyte differentiation blockage. T21 enhanced the proliferative phenotype, reproducing the cellular and molecular abnormalities of DS-AMKL. Our study provides an array of human cell–based models revealing individual contributions of different mutations to DS-AMKL differentiation blockage, a major determinant of leukemic progression. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1172/JCI156290 |
| الاتاحة: | https://hal.science/hal-04441606 https://hal.science/hal-04441606v1/document https://hal.science/hal-04441606v1/file/156290.3-20230426154518-covered-e0fd13ba177f913fd3156f593ead4cfd.pdf https://doi.org/10.1172/JCI156290 |
| Rights: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.E88D3B1D |
| قاعدة البيانات: | BASE |
| DOI: | 10.1172/JCI156290 |
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