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KAT6A Chimeras Forms a Self-Reinforcing Epigenetic Module with NURF and MLL/COMPASS in AML [ChIPMNase]

ABSTRACT: KAT6A-CBP (K/C) and KAT6A-P300 (K/P) fusions are recurrent genetic alterations in acute myeloid leukemia(AML) that are associated with poor prognosis. The large size of these fusion proteins has posed challenges in developing preclinical models, limiting mechanistic studies. To address this, we employed a domain-focused truncation strategy to generate de novo murine models of K/C and K/P fusions, which faithfully recapitulate the morphological, immunophenotypic, and transcriptomic features of KAT6A-rearranged AML. Genomic profiling revealed that KAT6A fusions preferentially localize to H3K4me2/3-marked regions and interact with the Nucleosome Remodeling Factor (NURF), a critical H3K4me2/3 reader. Disrupting NURF-chromatin interactions impaired K/C recruitment to target loci and disrupted MLL/COMPASS-mediated H3K4me2 deposition, thereby establishing an epigenetic regulatory module involving KAT6A chimeras, NURF, and MLL/COMPASS. Concurrently, CBP/P300 inhibition reduced histone acetylation, chromatin accessibility, and genomic targeting of the module. Therapeutically, NURF inhibition induced cell cycle arrest and suppressed leukemia proliferation, while CBP/P300 inhibition promoted leukemia differentiation. Both strategies demonstrated promising efficacy in K/C murine models, with superior effects observed with combined NURF and CBP/P300 inhibition. These findings uncover a self-reinforcing epigenetic module centered on histone reader proteins and modifying enzymes, providing mechanistic insights into KAT6A-rearranged AML and identifying promising combinatorial therapeutic vulnerabilities.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299383 | GEO | 2025/06/24

REPOSITORIES: GEO

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Project description:Histone acetyltransferases (HAT) catalyze the acylation of lysine side chains and are implicated in diverse human cancers as both oncogenes and non-oncogene dependencies. Acetyl-CoA-competitive HAT inhibitors have garnered attention as potential cancer therapeutics and the first clinical trial for this class is ongoing (NCT04606446). Despite broad enthusiasm for these targets, notably including CBP/p300 and KAT6A/B, the potential mechanisms of therapeutic response and evolved drug resistance remain poorly understood. Using comparative transcriptional genomics, we found that the direct gene regulatory consequences of CBP/p300 HAT inhibition are indistinguishable in models of intrinsically hypersensitive and insensitive acute myeloid leukemia (AML). We therefore modelled acquired drug resistance using a forward genetic selection and identified dysregulation of coenzyme A (CoA) metabolism as a facile driver of resistance to HAT inhibitors. Specifically, drug resistance selected for mutations in PANK3, a pantothenate kinase that controls the rate limiting step in CoA biosynthesis. These mutations prevent negative feedback inhibition, resulting in drastically elevated concentrations of intracellular acetyl-CoA, which directly outcompetes drug-target engagement. This not only impacts the activity of structurally diverse CBP/p300 HAT inhibitors, but also agents related to an investigational KAT6A/B inhibitor that is currently in Phase-1 clinical trials. We further validated these results using a genome-scale CRISPR/Cas9 loss-of-function genetic modifier screen, which identified additional gene-drug interactions between HAT inhibitors and the CoA biosynthetic pathway. Top hits from the screen included the phosphatase, PANK4, which negatively regulates CoA production and therefore suppresses sensitivity to HAT inhibition upon knockout, as well as the pantothenate transporter, SLC5A6, which enhances sensitivity. Altogether, this work uncovers CoA plasticity as an unexpected but potentially class-wide liability of anti-cancer HAT inhibitors and will therefore buoy future efforts to optimize the efficacy of this new form of targeted therapy.

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KAT6A Chimeras Forms a Self-Reinforcing Epigenetic Module with NURF and MLL/COMPASS in AML [ChIPMNase]

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