HOXA9 Reprograms the Enhancer Landscape to Promote Leukemogenesis

Cancer Cell. 2018 Oct 8;34(4):643-658.e5. doi: 10.1016/j.ccell.2018.08.018. Epub 2018 Sep 27.


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.

Keywords: HOXA9; KMT2; MLL; acute leukemia; de novo enhancer; epigenetics; histone methylation; pioneer factor; transcription factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic
  • Enhancer Elements, Genetic / genetics
  • Homeodomain Proteins / genetics*
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Methylation
  • Promoter Regions, Genetic / genetics


  • Homeodomain Proteins
  • homeobox protein HOXA9