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Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome–associated leukemia

Individuals with Down syndrome (DS) have more than 100-fold increased risk of acute megakaryoblastic leukemia (AMKL), but its pathogenesis is poorly understood. In this issue of the JCI, Arkoun et al. engineered stepwise DS-AMKL–associated mutations in GATA1, MPL, and SMC3 in human induced pluripote...

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Autores principales: Evans, Edward J., DeGregori, James
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9282920/
https://www.ncbi.nlm.nih.gov/pubmed/35838049
http://dx.doi.org/10.1172/JCI161659
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author Evans, Edward J.
DeGregori, James
author_facet Evans, Edward J.
DeGregori, James
author_sort Evans, Edward J.
collection PubMed
description Individuals with Down syndrome (DS) have more than 100-fold increased risk of acute megakaryoblastic leukemia (AMKL), but its pathogenesis is poorly understood. In this issue of the JCI, Arkoun et al. engineered stepwise DS-AMKL–associated mutations in GATA1, MPL, and SMC3 in human induced pluripotent stem cell (iPSC) clones from individuals with DS to dissect how each mutation affects gene expression control and megakaryocytic differentiation. The authors showed that the mutations cooperatively promote progression from transient myeloproliferative disorder to DS-AMKL. This study highlights the importance of mutation order and context in the perturbations of transcriptional and differentiation pathways involved in the evolution of hematologic malignancies, which will be critical for the development of preventative and therapeutic interventions.
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spelling pubmed-92829202022-07-18 Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome–associated leukemia Evans, Edward J. DeGregori, James J Clin Invest Commentary Individuals with Down syndrome (DS) have more than 100-fold increased risk of acute megakaryoblastic leukemia (AMKL), but its pathogenesis is poorly understood. In this issue of the JCI, Arkoun et al. engineered stepwise DS-AMKL–associated mutations in GATA1, MPL, and SMC3 in human induced pluripotent stem cell (iPSC) clones from individuals with DS to dissect how each mutation affects gene expression control and megakaryocytic differentiation. The authors showed that the mutations cooperatively promote progression from transient myeloproliferative disorder to DS-AMKL. This study highlights the importance of mutation order and context in the perturbations of transcriptional and differentiation pathways involved in the evolution of hematologic malignancies, which will be critical for the development of preventative and therapeutic interventions. American Society for Clinical Investigation 2022-07-15 2022-07-15 /pmc/articles/PMC9282920/ /pubmed/35838049 http://dx.doi.org/10.1172/JCI161659 Text en © 2022 Evans et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Commentary
Evans, Edward J.
DeGregori, James
Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome–associated leukemia
title Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome–associated leukemia
title_full Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome–associated leukemia
title_fullStr Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome–associated leukemia
title_full_unstemmed Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome–associated leukemia
title_short Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome–associated leukemia
title_sort dissecting stepwise mutational impairment of megakaryopoiesis in a model of down syndrome–associated leukemia
topic Commentary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9282920/
https://www.ncbi.nlm.nih.gov/pubmed/35838049
http://dx.doi.org/10.1172/JCI161659
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