期刊
CELLS
卷 12, 期 8, 页码 -出版社
MDPI
DOI: 10.3390/cells12081195
关键词
MLL-AF9; induced pluripotent stem cells (iPSCs); hematopoiesis; myeloid; differentiation; bioinformatics; oncogene
类别
A translocation at 9;11(p22;q23) leads to the formation of MLL-AF9 fusion protein, which is found in 25% of de novo AML cases in children. Using a hiPSC model with doxycycline-dependent MLL-AF9 expression, we investigated the effects of MLL-AF9 on hematopoietic development and its transformation to (pre-)leukemic states. We observed disruptions in early myelomonocytic development and identified gene profiles consistent with primary MLL-AF9 AML.
A t(9;11)(p22;q23) translocation produces the MLL-AF9 fusion protein, which is found in up to 25% of de novo AML cases in children. Despite major advances, obtaining a comprehensive understanding of context-dependent MLL-AF9-mediated gene programs during early hematopoiesis is challenging. Here, we generated a human inducible pluripotent stem cell (hiPSC) model with a doxycycline dose-dependent MLL-AF9 expression. We exploited MLL-AF9 expression as an oncogenic hit to uncover epigenetic and transcriptomic effects on iPSC-derived hematopoietic development and the transformation into (pre-)leukemic states. In doing so, we observed a disruption in early myelomonocytic development. Accordingly, we identified gene profiles that were consistent with primary MLL-AF9 AML and uncovered high-confidence MLL-AF9-associated core genes that are faithfully represented in primary MLL-AF9 AML, including known and presently unknown factors. Using single-cell RNA-sequencing, we identified an increase of CD34 expressing early hematopoietic progenitor-like cell states as well as granulocyte-monocyte progenitor-like cells upon MLL-AF9 activation. Our system allows for careful chemically controlled and stepwise in vitro hiPSC-derived differentiation under serum-free and feeder-free conditions. For a disease that currently lacks effective precision medicine, our system provides a novel entry-point into exploring potential novel targets for personalized therapeutic strategies.
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