HOXA9 Reprograms the Enhancer Landscape to Promote Leukemogenesis

Yuqing Sun, Bo Zhou, Fengbiao Mao, Jing Xu, Hongzhi Miao, Zhenhua Zou, Le Tran Phuc Khoa, Younghoon Jang, Sheng Cai, Matthew Witkin, Richard Koche, Kai Ge, Gregory R. Dressler, Ross L. Levine, Scott A. Armstrong, Yali Dou, Jay L. Hess

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Aberrant expression of HOXA9 is a prominent feature of acute leukemia driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid and B progenitor cells leads to significant enhancer reorganizations with prominent emergence of leukemia-specific de novo enhancers. Alterations in the enhancer landscape lead to activation of an ectopic embryonic gene program. We show that HOXA9 functions as a pioneer factor at de novo enhancers and recruits CEBPα and the MLL3/MLL4 complex. Genetic deletion of MLL3/MLL4 blocks histone H3K4 methylation at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis in vivo. These results suggest that therapeutic targeting of HOXA9-dependent enhancer reorganization can be an effective therapeutic strategy in acute leukemia with HOXA9 overexpression. Sun et al. show that HOXA9 overexpression in myeloid and B progenitor cells induces emergence of leukemia-specific enhancers by recruiting CEBPα and the MLL3/MLL4 complex, leading to activation of an ectopic embryonic gene program. Genetic deletion of MLL3/MLL4 inhibits HOXA9/MEIS1-mediated leukemogenesis.

Original languageEnglish (US)
Pages (from-to)643-658.e5
JournalCancer Cell
Volume34
Issue number4
DOIs
StatePublished - Oct 8 2018

Keywords

  • HOXA9
  • KMT2
  • MLL
  • acute leukemia
  • de novo enhancer
  • epigenetics
  • histone methylation
  • pioneer factor
  • transcription factor

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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