Description
DNMT3A is one of several epigenetic modifiers identified as recurrently mutated in acute myeloid leukemia (AML). DNMT3A mutations are associated with cytogenetically normal AML. In vitro experiments indicate that the R882H mutation acts in a dominant negative manner to disrupt the de novo methyltransferase activity of wildtype homotetramers. AML patient bone marrow harboring R882 mutations were similarly demonstrated to be hypomethylated compared to patients with wildtype DNMT3A. These studies also indicated that non-R882 DNMT3A mutations may act in a functionally distinct manner from R882 mutations. Alternative mechanisms indicate independent prognostic outcomes and treatment protocols may need to be considered for these two classes of DNMT3A mutations.