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Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome–associated leukemia
Edward J. Evans Jr., James DeGregori
Edward J. Evans Jr., James DeGregori
Published July 15, 2022
Citation Information: J Clin Invest. 2022;132(14):e161659. https://doi.org/10.1172/JCI161659.
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Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome–associated leukemia

Abstract

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.

Authors

Edward J. Evans Jr., James DeGregori

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