Analysis of chromatin accessibility relative to epigenetic features of azacitidine response in high-risk myelodysplastic syndrome

Azacitidine is used to treat patients with myelodysplastic syndrome, which alters epigenetic regulatory program that changes global gene expression by inhibiting DNA methylation. However, epigenomic factors affecting azacitidine response have not been studied in the context of chromatin. The efficacy of the hypomethylating agent differs by patient, leaving approximately 40% of patients fail to respond. Here, we demonstrate that chromatin accessibility features in patient-derived bone marrow cells can distinguish azacitidine responders from non-responders before treatment. Profiling chromatin accessibility from 23 high-risk myelodysplastic syndrome patients discovered that treatment response is strongly associated with distinct hematopoietic cell states. While non-responders showed enrichment of myeloid progenitor signatures, responders were characterized by elevated T cell populations. Notably, CD8+ T cells from non-responders exhibited selective loss of chromatin accessibility at TBX/EOMES binding sites, revealing a previously unrecognized link between T cell differentiation state and azacitidine response. These findings suggest the importance of immune cell differentiation and their activity in hypomethylating agent response for myelodysplastic syndromes, providing insights for patient stratification and treatment optimization based on the chromatin accessibility in high-risk myelodysplastic syndrome patients. Bulk ATAC-seq profiling of bone marrow collected from high-risk myelodysplastic syndrome patients, acute myeloid leukemia patients, healthy donors. when they are diagnosed, before treatment using azacitidine. The patients can be grouped into azacitidine responders and non-responders. ATAC-seq profiling of CD4+ T cells and CD8+ T cells from high-risk myelodysplastic syndrome patients. The patients can be grouped into azacitidine responders and non-responders. *************************************************************** Raw files for human/patient samples were not submitted to GEO due to concerns about submitting personally identifiable sequence data for open access. ***************************************************************