Epigenetic Remodeling of BCOR-PRC1.1 Complex Dictates Response to IDH Inhibitors in AML

Background: IDH1/2 mutations occur in about 20% of AML and generate 2-hydroxyglutarate, which blocks TET-mediated hydroxymethylation, induces CpG island hypermethylation, and enforces a differentiation arrest. Although mutant-specific IDH inhibitors induce remissions, relapse is common. Our prior study identified recurrent acquisition of BCOR Loss of Function mutations at resistance. Because BCOR/PRC1.1 recruitment is regulated by CpG methylation, we hypothesized that IDH-driven hypermethylation disrupts BCOR binding, that IDH inhibitor mediated demethylation restores PRC1.1 occupancy, and that relapse associated BCOR loss prevents this restoration. Methods: Using isogenic TF-1 IDH2-R140Q models, we performed EvoC 6-base sequencing, BCOR ChIP-seq, and RNA-seq across WT, IDH2 mutant, and enasidenib treated cells. Published CRISPR-Cas9 screening data from IDH1 mutant AML (Liu et al. Cancer Research 2022) were reanalyzed to define major key genes in IDH-inhibitor-induced differentiation. Results: IDH2 mutation induced coordinated promoter hypermethylation and 5hmC loss. EvoC sequencing showed that about 60% of DMRs were hypermethylated and enriched upstream of transcription start sites. 5hmC was markedly reduced and fully restored by enasidenib, consistent with impaired TET2 activity. Notably, 87% of hypermethylated DMRs with 5hmC loss underwent demethylation after 28 days of treatment, coinciding with normalized 2HG. BCOR occupancy decreased at promoter-proximal regions in IDH2 mutant cells and was restored by enasidenib.Integration of methylation, BCOR ChIP-seq, and RNA-seq showed that most BCOR-loss promoters were hypermethylated, transcriptionally activated, and normalized with treatment. Restored BCOR targets were enriched for Wnt, PI3K/Akt/mTOR, RTK, and MAPK pathways. Promoters of JUNB and WNT11 showed concordant hypermethylation, reduced BCOR binding, and increased expression in IDH2 mutant cells, all reversed by enasidenib.CRISPR-Cas9 data identified Bcor as a top gene required for differentiation upon IDH inhibition, exceeding canonical regulators such as Cebpa and Cebpb. Bcor targets (Junb and Wnt11) also ranked as essential effectors in the differentiation arm, matching our multi-omics findings. Conclusions: IDH2 mutation establishes an epigenetic blockade marked by promoter hypermethylation, 5hmC loss, and loss of BCOR-PRC1.1 occupancy, enabling aberrant activation of stemness programs. Enasidenib reverses these defects by restoring 5hmC, promoter methylation balance, BCOR binding, and PRC1.1-mediated repression. These data support a model in which IDH-inhibitor-induced differentiation requires intact BCOR function and repression of BCOR targets such as JUNB and WNT11, defining how IDH-mutant epigenetic dysregulation and BCOR loss converge to limit therapeutic efficacy. Citation Format: Sarah Hanache, Xiaoyan Zhang, Satoko Ogata, Hidetaka Uryu, Ken Furudate, Zongrui Li, Abhinav Jain, Erika Thompson, Courtney D. Dinardo, Margaret A. Goodell, Koichi Takahashi. Epigenetic remodeling of BCOR-PRC1.1 complex dictates response and resistance to IDH inhibitors in AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1962.