Abstract 217: Analysis of chromatin accessibility profiling reveals epigenetic features of azacitidine response in high-risk myelodysplastic syndrome

Abstract Azacitidine, a hypomethylating agent, is currently represented as initial therapy in most cases of high-risk myelodysplastic syndromes (MDS), yet only 40-60% of patients achieve therapeutic response. Non-responders face poor outcomes and disease progression to secondary acute myeloid leukemia. To improve treatment outcomes, understanding the pre-treatment molecular determinants of azacitidine response is critical. Despite the fundamental role of epigenetic regulation and cellular composition in MDS, the complex interplay between epigenetic regulation and therapeutic response has not been investigated. Here, we analyzed chromatin accessibility landscapes of 23 high-risk MDS patients before getting azacitidine, using Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq). We identified 1, 940 distinct chromatin accessibility features strongly associated with azacitidine response, suggesting gene regulatory elements like enhancers as key determinants of it. Also, non-responders exhibited significant myeloid lineage commitment, while responders showed elevated accessibility in regions governing immune activation and T cell differentiation pathways. Notably, T cell subsets of non-responders displayed distinct chromatin states associated with impaired cellular differentiation compared to responders and healthy donors. This study first establishes chromatin accessibility features as potential biomarkers for azacitidine response in high-risk MDS and provides novel insights for personalized treatment optimization. Citation Format: Dayoung Kim, Silvia Park, Yoo Jin Kim, Ryan Corces, Seung Woo Cho. Analysis of chromatin accessibility profiling reveals epigenetic features of azacitidine response in high-risk myelodysplastic syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 217.