The Implications of DNMT Mutations and the Prognostic and Therapeutic Relevance of DNMTis in AML: A Literature Review

Abstract

Introduction: Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive form of blood cancer characterized by the halted differentiation and proliferation of hematopoietic stem cells (HSCs). Normal hematopoietic functioning is regulated by DNA methyltransferase (DNMT) enzymes which modify the DNA epigenetic landscape. DNMT malfunction is associated with AML, therefore, DNMT inhibitors (DNMTis), such as azacytidine, are being investigated as a potential treatment option for AML patients. This literature review aims to identify the implications of DNMT mutations in AML and the therapeutic value of DNMTis.

Methods: A literature search was conducted using databases including the York University library and PubMed using keywords such as “AML”, “DNMT”, “DMNTi”. Studies were restricted to publication dates between 2010 to 2024.

Results: DNMT3A mutations, specifically at Arginine 882, are common amongst AML patients. Additionally, ten-eleven translocation methylcytosine dioxygenase 2 (TET2) mutations correlate with AML incidence. Reduced catalytic activity of DNMTs caused by mutations can cause hypomethylation and increased gene transcription or hypermethylation and decreased gene transcription. Depending on the patient genome and responsiveness, DNMTis promote normal cell functioning in malignant cells. Aberrant HSC clonal expansion and proliferation within the bone marrow leads to dysregulated hematopoiesis. This characteristic of AML is correlated with DNMT mutations.

Discussion: DNMTis have high therapeutic potential because of their ability to reverse aberrant DNMT methylation patterns while having synergistic effects alongside other treatments. Also, DNA methylation pattern sequencing, such as chromatin accessibility studies, can be useful as predictive biomarkers for AML. The research limitations include navigating the complexity of AML and the variability of responses to DNMTi therapies. Future research should investigate patient biomarkers which could tailor treatment options.

Conclusion: The mortality and complexity of AML warrant further investigation into its underlying causes and potential treatments. As a combinatorial and generally well-tolerated treatment, DNMTis are highly promising. Genomic testing that includes methylation level assessment is vital in appropriately detecting biomarkers that can direct patient treatment plans.