Among the most common mutations in AML are those affecting epigenetic regulators, particularly DNA methyltransferase 3A (DNMT3A) which are essential for the progression of leukemia. DNMT3A is critical for the establishing and maintaining of DNA methylation patterns. Mutations in DNMT3A alter the patient’s methylation patterns, leading to aberrant gene expression and consequently enhanced leukemogenesis. Hypomethylating agents, such as azacitidine and decitabine, are approved for AML therapy aiming to restore normal gene regulation by impacting methylation patterns within AML cells.
Current research indicates that methylation changes also affect the formation of alternative structures within the chromatin. Among those structures are G-quadruplexes, which can also influence gene expression (mainly from oncogenes) and chromatin formation. Further methylation of G-quadruplex motifs directly influences the formation of these structures, affecting gene expression. However, a direct mechanism of how these therapeutic agents affect the chromatin is not yet established. In our ongoing work, we investigated within the blood of 62 AML patients how hypomethylating agents modify the chromatin landscape by affecting the formation of alternative DNA structures such as G-quadruplex. Our preliminary investigation reveals elevated G4 levels in AML compared to healthy counterparts, suggesting a potential link between G4 formation and the aberrant epigenetic landscape observed in AML. To further investigate the role of DNMT3A on alternative DNA structures in AML, a mouse model will be established. Based on our preliminary data we propose that DNA methylation changes influence the formation of alternative DNA structures, which directly affect chromatin status and gene expression changes and impact the progression of AML.