KAT6A and ENL Form an Epigenetic Transcriptional Control Module to Drive Critical Leukemogenic Gene-Expression Programs

Cancer Discov. 2022 Mar 1;12(3):792-811. doi: 10.1158/2159-8290.CD-20-1459.


Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene-expression programs. We show that KAT6A is the initiator of a newly described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyl-lysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small-molecule inhibitors could be of high therapeutic interest for mono-therapy or combinatorial differentiation-based treatment of AML.

Significance: AML is a poor-prognosis disease characterized by differentiation blockade. Through a cell-fate CRISPR screen, we identified KAT6A as a novel regulator of AML cell differentiation. Mechanistically, KAT6A cooperates with ENL in a "writer-reader" epigenetic transcriptional control module. These results uncover a new epigenetic dependency and therapeutic opportunity in AML. This article is highlighted in the In This Issue feature, p. 587.

Publication types

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

MeSH terms

  • Chromatin / genetics
  • Epigenesis, Genetic
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Neoplasm Proteins
  • Nuclear Proteins
  • Oncogenes*
  • Transcription Factors


  • Chromatin
  • MLLT1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Transcription Factors
  • Histone Acetyltransferases
  • KAT6A protein, human