The R882H DNMT3A Mutation Associated with AML Dominantly Inhibits Wild-Type DNMT3A by Blocking Its Ability to Form Active Tetramers

David A. Russler-Germain, David H. Spencer, Margaret A. Young, Tamara L. Lamprecht, Christopher A. Miller, Robert Fulton, Matthew R. Meyer, Petra Erdmann-Gilmore, R. Reid Townsend, Richard K. Wilson, Timothy J. Ley

Research output: Contribution to journalArticlepeer-review

250 Scopus citations

Abstract

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. Invitro 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.

Original languageEnglish
Pages (from-to)442-454
Number of pages13
JournalCancer Cell
Volume25
Issue number4
DOIs
StatePublished - Apr 14 2014

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