Abstract
Myelodysplastic syndromes and acute myeloid leukemia are heterogeneous hematologic malignancies characterized by clonal expansion of abnormal hematopoietic stem and progenitor cells, ineffective hematopoiesis, genomic instability, and progressive bone marrow failure. Increasing evidence has demonstrated that epigenetic dysregulation-including aberrant DNA methylation, histone modifications, chromatin remodeling, and altered non-coding RNA expression-plays a central role in disease initiation, progression, therapeutic resistance, and leukemic transformation. Unlike irreversible genetic mutations, epigenetic alterations are potentially reversible, making them attractive therapeutic targets. Hypomethylating agents such as azacitidine and decitabine have become the cornerstone of treatment for higher-risk MDS and elderly or medically unfit patients with AML. More recently, novel epigenetic therapies targeting histone deacetylases, enhancer of zeste homolog 2 (EZH2), lysine-specific demethylase 1 (LSD1), bromodomain and extra-terminal (BET) proteins, and mutant isocitrate dehydrogenase (IDH) pathways have demonstrated promising clinical activity. Combination strategies integrating epigenetic agents with targeted therapies, BCL-2 inhibitors, immunotherapy, and cellular therapies are further improving treatment outcomes.