Lv Junhui, Yin Zhinang, Li Conghui, Wen Honglin, Ni Jian, Yang Peiyuan, Song Zemin, Xiang Ying, Wang Honghong, Lu Rui, Huang Li, Zhou Ying, Zhou Hai-Bing, Xiao Ruijing, Fang Pingping, Liang Kaiwei
State Key Laboratory of Metabolism and Regulation in Complex Organisms, TaiKang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, 115 DongHu Road, Research Building III, Room 404, Wuchang District, Wuhan, 430071, China.
State Key Laboratory of Virology and Biosafety, Frontier Science Center for Immunology and Metabolism, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
Genome Biol. 2025 Aug 19;26(1):253. doi: 10.1186/s13059-025-03743-y.
KAT6A-CBP (K/C) and KAT6A-P300 (K/P) fusions are recurrent genetic alterations in acute myeloid leukemia (AML) associated with poor prognosis. Despite their strong oncogenic potential, the mechanisms underlying their genomic targeting and leukemogenic function remain unclear. A major challenge has been their large size, which has impeded preclinical model development and mechanistic studies.
We employ 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 reveals that KAT6A fusions preferentially localize to H3K4me2/3-marked regions, while biochemical analyses uncover that KAT6A interacts with the Nucleosome Remodeling Factor (NURF), a key H3K4me2/3 reader. Disrupting NURF-chromatin interactions via depletion or small-molecule inhibition of its subunit, Bromodomain PHD Finger Transcription Factor (BPTF), impairs K/C recruitment and disrupts MLL/COMPASS-mediated H3K4me2 deposition, defining a functional epigenetic module involving KAT6A chimeras, NURF, and MLL/COMPASS. Notably, CBP/P300 inhibition reduces histone acetylation and chromatin accessibility, further impairing the recruitment of this epigenetic module. Targeting this module via NURF or CBP/P300 inhibition demonstrates efficacy in K/C leukemia models, with enhanced therapeutic effects observed when combined.
Our study identifies a self-reinforcing epigenetic module of histone modifiers and readers in KAT6A-rearranged AML, providing mechanistic insights into the genomic targeting of KAT6A chimeras and highlighting promising combinatorial therapeutic strategies.
KAT6A-CBP（K/C）和KAT6A-P300（K/P）融合是急性髓系白血病（AML）中反复出现的基因改变，与预后不良相关。尽管它们具有强大的致癌潜力，但其基因组靶向和致白血病功能的潜在机制仍不清楚。一个主要挑战是它们的片段较大，这阻碍了临床前模型的开发和机制研究。
我们采用聚焦结构域的截短策略来生成K/C和K/P融合的全新小鼠模型，这些模型忠实地再现了KAT6A重排AML的形态、免疫表型和转录组特征。基因组分析表明，KAT6A融合优先定位于H3K4me2/3标记的区域，而生化分析发现KAT6A与核小体重塑因子（NURF）相互作用，NURF是一种关键的H3K4me2/3阅读器。通过耗尽或小分子抑制其亚基溴结构域PHD指转录因子（BPTF）来破坏NURF-染色质相互作用，会损害K/C募集并破坏MLL/COMPASS介导的H3K4me2沉积，从而定义了一个涉及KAT6A嵌合体、NURF和MLL/COMPASS的功能性表观遗传模块。值得注意的是，CBP/P300抑制会降低组蛋白乙酰化和染色质可及性，进一步损害该表观遗传模块的募集。通过抑制NURF或CBP/P300靶向该模块在K/C白血病模型中显示出疗效，联合使用时观察到增强的治疗效果。
我们的研究在KAT6A重排的AML中鉴定出一个由组蛋白修饰剂和阅读器组成的自我强化表观遗传模块，为KAT6A嵌合体的基因组靶向提供了机制见解，并突出了有前景的联合治疗策略。
