This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Epigenetic Regulation in Acute Myeloid Leukemia: Molecular Mechanisms and Clinical Implications
Cancer Research UK, Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
*
Authors to whom correspondence should be addressed.
Cancers 2026, 18(14), 2203; https://doi.org/10.3390/cancers18142203
Submission received: 29 May 2026
/
Revised: 1 July 2026
/
Accepted: 3 July 2026
/
Published: 8 July 2026
(This article belongs to the Special Issue Clinical Treatment and Translational Advances in Myelodysplastic Syndromes and Acute Myeloid Leukemia)
Simple Summary
Epigenetics is the study of heritable changes in gene expression that do not alter the underlying DNA sequence. In acute myeloid leukemia (AML), these regulatory mechanisms are frequently dysregulated, driving uncontrolled proliferation and blocking normal myeloid differentiation. This review systematically examines the principal layers of epigenetic regulation, including DNA methylation, histone modifications, chromatin remodeling, and RNA-mediated epigenetics. We describe how their disruption contributes to AML pathogenesis, with particular emphasis on how recurrent genetic lesions such as DNMT3A mutations and KMT2A (MLL) rearrangements shape the epigenetic landscape of the disease. We further discuss current therapeutic options for AML, with a focus on approved agents and ongoing clinical trials targeting epigenetic regulators.
Abstract
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by a block of differentiation and uncontrolled expansion of myeloid progenitor cells. Standard treatment includes intensive induction chemotherapy, typically with cytarabine and anthracycline, followed by consolidation chemotherapy or allogeneic hematopoietic stem cell transplantation. However, these approaches are often associated with relapse and treatment-related toxicity. Accumulating evidence highlights a critical role for epigenetic dysregulation in driving disease initiation, progression, and therapeutic resistance. In this review, we examine an integrated framework of epigenetic regulation in AML, encompassing DNA methylation, histone post-translational modifications, chromatin remodeling, and RNA-mediated epigenetics. We discuss how alterations in key epigenetic regulators, such as DNMT3A, TET2, IDH1/2, EZH2, and histone-modifying enzymes, reshape the transcriptional and epigenetic landscape of leukemic cells. Particular emphasis is placed on epigenetically defined AML subtypes, including NPM1-mutated, DNMT3A-mutated, and KMT2A-rearranged AML, which illustrate distinct mechanisms of transcriptional and epigenetic dysregulation and confer unique therapeutic vulnerabilities. We further summarize current and emerging therapeutic strategies, ranging from conventional chemotherapy to molecularly targeted agents, epigenetic drugs, and immunotherapeutic approaches. Despite these advances, durable responses remain limited, highlighting the need to better understand epigenetic mechanisms to overcome resistance and improve patient outcomes.
