Association of DNA methyltransferase 3A gene expression and polymorphisms with chronic myeloid leukemia susceptibility in an Iraqi cohort

Abstract: BACKGROUND: While somatic DNA methyltransferase 3A (DNMT3A) mutations are known to drive hematological malignancies, the role of DNMT3A genetic variants and expression changes in chronic myeloid leukemia (CML) remains poorly understood, particularly in the context of tyrosine kinase inhibitor (TKI) therapy. OBJECTIVES: This study aimed to investigate the association of DNMT3A gene expression levels and two specific polymorphisms within its catalytic domain with the risk of CML and the clinical response to bosutinib therapy in a cohort of Iraqi patients. PATIENTS, MATERIALS, AND METHODS: In this cross-sectional study, 40 CML patients (20 responsive and 20 nonresponsive to bosutinib) and 20 healthy controls were enrolled. DNMT3A mRNA expression was quantified using quantitative real-time polymerase chain reaction. RESULTS: DNMT3A expression was significantly downregulated in CML patients compared to healthy controls ( P = 0.003), irrespective of their response to bosutinib. The heterozygous (AG) genotype at rs2149275458 and the homozygous (CC) genotype at the other variant were significantly associated with CML susceptibility ( P < 0.0001 for both) but not with treatment response. The corresponding C alleles for both single-nucleotide polymorphisms were identified as significant risk factors for the disease. CONCLUSION: DNMT3A polymorphisms and reduced DNMT3A expression were significantly associated with CML, suggesting a potential role for this epigenetic regulator in disease biology. While these variants may serve as biomarkers for CML susceptibility, the observed downregulation could represent a pharmacodynamic effect of TKI treatment. These findings warrant further investigation into their functional roles and clinical utility.