Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome–associated leukemia
Year: 2022
Type: article
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.
DOI: 10.1172/jci161659
Authors: Edward J. Evans, James DeGregori
Institution: University of Colorado Anschutz
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: National Institutes of Health, National Cancer Institute, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Anschutz Medical Campus
OpenAlex ID: W4285385682