R882H DNMT3A Causes Dominant-Negative Inhibition Of WT DNMT3A

Mutations in DNMT3A(encoding one of two mammalian de novoDNA methyltransferases) are found in >30% of normal karyotype AML cases and correlate with poor clinical outcomes. Most DNMT3Amutations occur at position R882 within the catalytic domain (most commonly R882H) and are virtually always heterozygous. This over-representation suggests that mutations at R882 may result in gain-of-function or dominant-negative activity that contributes to leukemogenesis. However, how DNA methylation might be altered in DNMT3A-mutant cases of AML remains unclear, and no published study to date has addressed the effects of mixing wild-type (WT) and R882H DNMT3A. Importantly, mouse HSPCs deficient in Dnmt3adramatically expand over time and have a concurrent defect in differentiation (Challen, GA et al. Nat Genet, 2011). Mice haploinsufficient for Dnmt3a, on the other hand, do not have a measurable defect in hematopoiesis. Collectively, these data suggest that the heterozygous R882 mutations probably cause more than a simple loss-of-function phenotype.