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

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. 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

Metabolic adaptations underpin resistance to histone acetyltransferase inhibition

“…PF-07248144, an inhibitor of the structurally distinct MYST HAT domains of KAT6A/B, is currently being evaluated in Phase I clinical trials for treatment-refractory breast cancer (NCT04606446). KAT6A has also been described as a dependency in AML 16 , so we determined if modulating acetyl-CoA levels could shift sensitivity to MYST inhibition in AML cell lines. Indeed, overexpressing PANK3 and PANK3 G193A in MOLM-13 cells conferred resistance to the KAT6A/B inhibitor, PF-9363 45 (Fig.…”

“…They are also recurrently mutated in lymphomas and lung cancers resulting in a synthetic lethality between the two paralogs 15 . Likewise, several MYST-family HAT proteins, such as KAT6A/B and HBO1, are involved in oncogenic fusions and/or are required for the maintenance of tumorigenic gene expression 10,16,17 . These genetic data have motivated widespread efforts to address HAT proteins with chemical probe discovery and drug development.…”

OCRL is a novel prognostic biomarker and its association with immunoregulation in breast cancer

“…DNA methylation was a kind of epigenetic regulation of gene to silence the expression of genes [30]. In this study, we investigated the DNA methylation of OCRL to understand the underlying regulation mechanisms of OCRL expression.…”

Hox‐driven conditional immortalization of myeloid and lymphoid progenitors: Uses, advantages, and future potential

“…Ma et al used genetically manipulated Hoxb8 ‐immortalized eosinophils to study actin polymerization of eosinophils in neoplastic hypereosinophilia 47 . These Hox ‐derived cells have been used in a number of large screens, speaking to their flexibility and utility 72,73 . These cells have also been used recently in a few epigenetic studies, speaking to their utility in studying cell‐fate decisions 74,75 .…”

“…47 These Hox-derived cells have been used in a number of large screens, speaking to their flexibility and utility. 72,73 These cells have also been used recently in a few epigenetic studies, speaking to their utility in studying cell-fate decisions. 74,75 These studies demonstrate that Hoxmediated conditional immortalization of immune-cell progenitors provides a useful resource beyond purely immunological studies, and as we gain more insight into the biology of HSC-derived immune cells, the wider the scope of this system will grow.…”