Hematopoietic differentiation is required for initiation of acute myeloid leukemia Journal Article

Authors: Ye, M.; Zhang, H.; Yang, H.; Koche, R.; Staber, P. B.; Cusan, M.; Levantini, E.; Welner, R. S.; Bach, C. S.; Zhang, J.; Krivtsov, A. V.; Armstrong, S. A.; Tenen, D. G.
Article Title: Hematopoietic differentiation is required for initiation of acute myeloid leukemia
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. © 2015 Elsevier Inc.
Journal Title: Cell Stem Cell
Volume: 17
Issue: 5
ISSN: 1934-5909
Publisher: Cell Press  
Date Published: 2015-11-05
Start Page: 611
End Page: 623
Language: English
DOI: 10.1016/j.stem.2015.08.011
PROVIDER: scopus
PMCID: PMC4636971
PUBMED: 26412561
Notes: Export Date: 2 December 2015 -- Source: Scopus
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MSK Authors
  1. Scott Allen Armstrong
    108 Armstrong
  2. Monica Cusan
    12 Cusan
  3. Richard Patrick Koche
    56 Koche