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

Fangxue Yan, Jinyang Li, Jelena Milosevic, Ricardo Petroni, Suying Liu, Zhennan Shi, Salina Yuan, Janice M. Reynaga, Yuwei Qi, Joshua Rico, Sixiang Yu, Yiman Liu, Susumu Rokudai, Neil Palmisiano, Sara E. Meyer, Pamela J. Sung, Liling Wan, Fei Lan, Benjamin A. Garcia, Ben Z. StangerDavid B. Sykes, M. Andrés Blanco

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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. Mecha-nistically, KAT6A cooperates with ENL in a “writer–reader” epigenetic transcriptional control module. These results uncover a new epigenetic dependency and therapeutic opportunity in AML.

Original languageEnglish
Pages (from-to)792-811
Number of pages20
JournalCancer discovery
Volume12
Issue number3
DOIs
StatePublished - Mar 1 2022

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