The R882H DNMT3A Mutation Associated with AML Dominantly Inhibits Wild-Type DNMT3A by Blocking Its Ability to Form Active Tetramers
Menée in vitro, cette étude met en évidence des mécanismes liés à la présence de la mutation R882H du gène DNMT3A, codant une méthyltransférase, dans les génomes de cellules de leucémie myéloïde aiguë
Somatic mutations in DNMT3A, which encodes a de novo DNA methyltransferase, are found in <30% of normal karyotype acute myeloid leukemia (AML) cases. Most mutations are heterozygous and alter R882 within the catalytic domain (most commonly R882H), suggesting the possibility of dominant-negative consequences. The methyltransferase activity of R882H DNMT3A is reduced by <80% compared with the WT enzyme. In vitro mixing of WT and R882H DNMT3A does not affect the WT activity, but coexpression of the two proteins in cells profoundly inhibits the WT enzyme by disrupting its ability to homotetramerize. AML cells with the R882H mutation have severely reduced de novo methyltransferase activity and focal hypomethylation at specific CpGs throughout AML cell genomes. "AML cases with DNMT3A mutations at R882 exhibit focal hypomethylation "R882H DNMT3A is a dominant-negative inhibitor of WT DNMT3A "WT DNMT3A forms stable, active homotetramers "R882H DNMT3A dominantly disrupts DNMT3A tetramerization Heterozygous DNMT3A R882H mutation is common in acute myeloid leukemia (AML). Russler-Germain et al. show that DNMT3AR882H inhibits wild-type DNMT3A activity in cells, but not in vitro, and that AML cells with the R882H mutation have reduced de novo methyltransferase activity and focal CpG hypomethylation.