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Abstract
Leukemia remains one of the most pressing global health concerns, with therapy resistance posing a persistent challenge across chemotherapy, targeted therapy, and immunotherapy. Increasing evidence reveals that epigenetic abnormalities including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA dysregulation play crucial roles in leukemogenesis, disease progression, and the emergence of drug resistance. These modifications form intricate regulatory networks that reprogram transcriptional landscapes, sustain leukemic stem cell self-renewal, and foster clonal adaptability under therapeutic stress. While single-agent epigenetic therapies have demonstrated limited efficacy, their combination with conventional chemotherapy, molecularly targeted drugs, or immunotherapies shows promise in enhancing therapeutic response and reducing relapse rates. Moreover, the advent of integrative multi-omics and spatial multi-omics technologies has enabled the identification of leukemia-specific epigenetic drivers and illuminated the heterogeneity of the leukemic microenvironment, opening new avenues for precision medicine. This review synthesizes current insights into the role of epigenetic dysregulation in leukemia progression and therapy resistance, evaluates the clinical potential of epigenetic-based therapeutic strategies, and discusses future challenges and opportunities in translating these approaches into personalized leukemia care.