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Cell Stem Cell. 2015 Nov 5;17(5):611-23. doi: 10.1016/j.stem.2015.08.011. Epub 2015 Sep 24.

Hematopoietic Differentiation Is Required for Initiation of Acute Myeloid Leukemia.

Author information

1
Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
2
Cancer Science Institute, National University of Singapore, Singapore, 117599.
3
Cancer Biology and Genetics Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, NY 10065, USA.
4
Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; Division of Hematology and Hemostaseology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, A-1090 Vienna, Austria.
5
Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; Institute of Biomedical Technologies, National Research Council, Pisa 56124, Italy.
6
Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany.
7
Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; Cancer Science Institute, National University of Singapore, Singapore, 117599. Electronic address: daniel.tenen@nus.edu.sg.

Abstract

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.

PMID:
26412561
PMCID:
PMC4636971
DOI:
10.1016/j.stem.2015.08.011
[Indexed for MEDLINE]
Free PMC Article

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