Hematopoietic Differentiation Is Required for Initiation of Acute Myeloid Leukemia

Academic Article

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.
  • Published In

  • Cell Stem Cell  Journal
  • Digital Object Identifier (doi)

    Author List

  • Ye M; Zhang H; Yang H; Koche R; Staber PB; Cusan M; Levantini E; Welner RS; Bach CS; Zhang J
  • Start Page

  • 611
  • End Page

  • 623
  • Volume

  • 17
  • Issue

  • 5