期刊
CELL STEM CELL
卷 28, 期 6, 页码 1074-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2021.01.011
关键词
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资金
- US National Institutes of Health (NIH) [R01HL137219, R01CA225231]
- New York State Stem Cell Board
- Pershing Square Sohn Cancer Research Alliance
- RUNX1 Research Program (RRP)/Alex's Lemonade Stand Foundation (ALSF), United States
- Leukemia and Lymphoma Society (LLS)
- NIH [U54 CA209975, R35HL135787, R01DK113639]
- LLS Blood Cancer Discovery Grant [8021-20]
- LLS Scholar Award
- CancerFree KIDS grant
- New York State Department of Health [NYSTEM-C32561GG]
- TriInstitutional Training Program in Computational Biology and Medicine (CBM) - NIH [1T32GM083937]
Through the combination of induced pluripotent stem cell (iPSC) and CRISPR-Cas9 technologies, a model of clonal evolution of acute myeloid leukemia (AML) was successfully developed. This model captured distinct premalignant stages and genetic features of primary human MDS and AML, ultimately identifying dysregulation of inflammatory signaling as an early and persistent event in leukemogenesis and a potential therapeutic target.
Human cancers arise through the sequential acquisition of somatic mutations that create successive clonal populations. Human cancer evolution models could help illuminate this process and inform therapeutic intervention at an early disease stage, but their creation has faced significant challenges. Here, we combined induced pluripotent stem cell (iPSC) and CRISPR-Cas9 technologies to develop a model of the clonal evolution of acute myeloid leukemia (AML). Through the stepwise introduction of three driver mutations, we generated iPSC lines that, upon hematopoietic differentiation, capture distinct premalignant stages, including clonal hematopoiesis (CH) and myelodysplastic syndrome (MDS), culminating in a transplantable leukemia, and recapitulate transcriptional and chromatin accessibility signatures of primary human MDS and AML. By mapping dynamic changes in transcriptomes and chromatin landscapes, we characterize transcriptional programs driving specific transitions between disease stages. We identify cell-autonomous dysregulation of inflammatory signaling as an early and persistent event in leukemogenesis and a promising early therapeutic target.
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