Epigenetic therapy in AML: network redundancy, resistance, and non-coding RNAs

Acute myeloid leukemia (AML) remains an aggressive hematologic malignancy sustained by dynamic epigenetic networks integrating DNA methylation, histone modifications, and ncRNA-linked chromatin-associated mechanisms. Collectively, these mechanisms enforce leukemic self-renewal, differentiation arrest, and therapeutic adaptation. Hypomethylating agents, IDH1/2 and menin inhibitors, and emerging chromatin-directed drugs have established epigenetic vulnerabilities as actionable therapeutic targets across genetically defined AML subsets. However, most clinical responses remain partial and transient, frequently limited by therapeutic resistance, functional redundancy within the epigenomic landscape, and the clonal plasticity that characterizes AML progression. This review synthesizes current evidence on how genetic context shapes epigenetic dependencies, therapeutic performance, and resistance mechanisms of established and emerging epigenetic therapies, with particular emphasis on the DNA methylation axis and chromatin/transcriptional complex-directed strategies. Within this framework, selected non-coding RNAs (ncRNAs) are considered as context-dependent modulators and potential biomarkers that intersect with epigenetic programs in specific settings, rather than as a separate epigenetic layer. Durable disease control will likely require rational combinations guided by biomarker-driven patient selection and integrated monitoring of epigenetic reprogramming, while ncRNA-based readouts may complement genomic and epigenomic markers in defined AML subsets.