Abstract 2960: KAT6A and ENL form an epigenetic transcriptional control module to drive critical leukemogenic gene expression programs

Abstract

Abstract Acute myeloid leukemia (AML) is a poor-prognosis hematological malignancy that is characterized by differentiation blockade and uncontrolled proliferation. Epigenetic programs influence AML cell fate decisions, and their mis-regulation can promote differentiation arrest. Itis therefore of paramount importance to identify the regulators of AML cell differentiation and understand the mechanisms by which they repress myeloid transcriptional programs. Here, we performed a cell-fate selection CRISPR screen for chromatin factors whose inhibition promotes AML cell differentiation. We found that the histone acetyltransferase KAT6A is a critical driver of the differentiation block, and that both genetic and chemical inhibition of KAT6A markedly de-repressed latent myeloid maturation programs, most commonly in MLL-rearranged AML. Inhibition of KAT6A catalytic activity reduced self-renewal, induced cell cycle arrest, and extinguished long-term proliferative capacity of AML cells. Through ChIP-seq, RNA-seq, and extensive analysis of clinical datasets, we found that KAT6A is the likely initiator of a newly-described "writer-reader" module that drives oncogenic gene expression in AML. In this model,KAT6A catalyzes promoter H3K9 acetylation, which is bound by the H3K9ac reader ENL, leading to Super elongation complex (SEC) recruitment and release of paused RNA PolII at oncogenic loci such as MYC. KAT6A is elevated in human AMLs compared to matched normal tissue, and its downregulation correlates with monocytic differentiation transcriptional programs in clinical AML datasets. These findings suggest the potential of targeting both KAT6A and ENL to disrupt this writer-reader module and ablate downstream MYC transcriptional programs inMLL-rearranged AML. Citation Format: Andres Blanco. KAT6A and ENL form an epigenetic transcriptional control module to drive critical leukemogenic gene expression programs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2960.