2. Academic Validation
  3. KAT6A chimeras form a self-reinforcing epigenetic module with NURF and MLL/COMPASS to sustain AML

KAT6A chimeras form a self-reinforcing epigenetic module with NURF and MLL/COMPASS to sustain AML

  • Genome Biol. 2025 Aug 19;26(1):253. doi: 10.1186/s13059-025-03743-y.
Junhui Lv # 1,  Zhinang Yin # 1,  Conghui Li # 1,  Honglin Wen # 1,  Jian Ni 2,  Peiyuan Yang 1,  Zemin Song 1,  Ying Xiang 1,  Honghong Wang 1,  Rui Lu 1,  Li Huang 3,  Ying Zhou 3,  Hai-Bing Zhou 2,  Ruijing Xiao 4,  Pingping Fang 5,  Kaiwei Liang 6 7
Affiliations

Affiliations

  • 1 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.
  • 2 State Key Laboratory of Virology and Biosafety, Frontier Science Center for Immunology and Metabolism, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
  • 3 Research Center for Medicine and Structural Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
  • 4 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. xrj7619@whu.edu.cn.
  • 5 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. pingpingfang@whu.edu.cn.
  • 6 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. kwliang@whu.edu.cn.
  • 7 Hubei Province Key Laboratory of Allergy and Immunology, Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China. kwliang@whu.edu.cn.
  • # Contributed equally.
PMID: 40830799 DOI: 10.1186/s13059-025-03743-y
Abstract

Background: 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.

Results: 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.

Conclusions: 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.

Keywords

AML; Acute myeloid leukemia; Chromatin accessibility; KAT6A; KAT6A-CBP; KAT6A-P300; MLL/COMPASS; NURF; Nucleosome Remodeling Factor.

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