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

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2014 Mar 25

PMID 24656771

Citations 246

Authors

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

Affiliations

Soon will be listed here.

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. 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.

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