期刊
CELL STEM CELL
卷 17, 期 5, 页码 611-623出版社
CELL PRESS
DOI: 10.1016/j.stem.2015.08.011
关键词
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资金
- National Institutes of Health [HL112719, CA66996, DK103858, P01CA066996]
- Singapore Ministry of Health's National Medical Research Council under Singapore Translational Research (STaR) Investigator Award
- National Research Foundation Singapore
- Singapore Ministry of Education under Research Centres of Excellence initiative
- FAMRI YCSA and CIA grant
- Austrian Research Foundation
- European Union
- Interdisciplinary Center for Clinical Research (IZKF) at the University Hospital of the University of Erlangen-Nuremberg
- German Research Foundation [BA 4186/1-1]
- Leukemia & Lymphoma Society (LLS)
- [P30 CA008748]
Mutations in acute myeloid leukemia (AML)-associated oncogenes often arise in hematopoietic stem cells (HSCs) and promote acquisition of leukemia stem cell (LSC) phenotypes. However, as LSCs often share features of lineage-restricted progenitors, the relative contribution of differentiation status to LSC transformation is unclear. Using murine MLL-AF9 and MOZ-TIF2 AML models, we show that myeloid differentiation to granulocyte macrophage progenitors (GMPs) is critical for LSC generation. Disrupting GMP formation by deleting the lineage-restricted transcription factor C/EBPa blocked normal granulocyte formation and prevented initiation of AML. However, restoring myeloid differentiation in C/EBPa mutants with inflammatory cytokines reestablished AML transformation capacity. Genomic analyses of GMPs, including gene expression and H3K79me2 profiling in conjunction with ATAC-seq, revealed a permissive genomic environment for activation of a minimal transcription program shared by GMPs and LSCs. Together, these findings show that myeloid differentiation is a prerequisite for LSC formation and AML development, providing insights for therapeutic development.
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