Abstract PR005: Targeting Chromatin–Cell Cycle Vulnerabilities in High-Risk Pediatric Acute Myeloid Leukemia

Abstract Background: Pediatric acute myeloid leukemias (AMLs) are driven by transcription factor (TF) fusions that reprogram the epigenome, creating fusion-specific subtypes with distinct biomarkers, prognoses, and vulnerabilities. Pediatric AMLs driven by the CBFA2T3::GLIS2 (C/G) fusion are among the highest-risk subtypes, with fewer than 15% patients surviving 60 months post-diagnosis. These dismal outcomes stem from an incomplete understanding of how C/G rewires chromatin to establish subtype-specific regulatory dependencies, limiting development of targeted therapies. Comprehensive, multi-omic dissection of oncofusion-driven gene regulation is essential to reveal druggable mechanistic vulnerabilities. Methods and Results: To detect C/G-interacting factors, we performed unbiased immunoprecipitation mass spectrometry (IP-MS) profiling of C/G in patient-derived AML cell lines. This revealed a novel interaction with mammalian SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes, which normally guide hematopoietic differentiation. CRISPR-based viability assays showed that C/G cell survival relies on BRG1-containing mSWI/SNF, revealing a fusion-specific chromatin remodeling dependency. To investigate how this interaction reprograms myeloid cells, we compared C/G-transformed hematopoietic stem and progenitor cells (HSPCs) to non-transformed counterparts. CUT&RUN profiling of C/G-mSWI/SNF occupancy and histone modifications, integrated with RNA-seq, showed that C/G retargets mSWI/SNF to oncogenic regulatory elements, sustaining overexpression of cell cycle genes CCND2 and CDK6. This C/G-directed chromatin remodeling creates a clinically targetable mSWI/SNF-G1 regulatory axis. Pharmacologic inhibition of this axis using palbociclib, an FDA-approved CDK4/6 kinase inhibitor, reduced leukemic burden and extended survival by ∼56% in an aggressive C/G AML mouse model, highlighting a clinically actionable vulnerability. Conclusions: These findings reveal how the C/G oncofusion repurposes BRG1-containing mSWI/SNF complexes to drive cell cycle gene activation, establishing a chromatin–cell cycle regulatory circuit that is selectively targetable through G1 restriction. This mechanistic insight provides a rationale for repurposing CDK4/6 inhibitors for children with this otherwise lethal AML subtype. Citation Format: Gabriel E. Boyle, Alexander W. Ying, Lara Yao, Chao-Jen Wong, Liam Caven, Morgan Merrill, Farzane Sivandzade, Matthew Wither, Soheil Meshinchi, Rachel Rau, Shan Lin, Cigall Kadoch, Jay F. Sarthy. Targeting Chromatin–Cell Cycle Vulnerabilities in High-Risk Pediatric Acute Myeloid Leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr PR005.