TY - JOUR
T1 - The R882H DNMT3A Mutation Associated with AML Dominantly Inhibits Wild-Type DNMT3A by Blocking Its Ability to Form Active Tetramers
AU - Russler-Germain, David A.
AU - Spencer, David H.
AU - Young, Margaret A.
AU - Lamprecht, Tamara L.
AU - Miller, Christopher A.
AU - Fulton, Robert
AU - Meyer, Matthew R.
AU - Erdmann-Gilmore, Petra
AU - Townsend, R. Reid
AU - Wilson, Richard K.
AU - Ley, Timothy J.
N1 - Funding Information:
The authors thank Daniel George and Anne Kettler for technical assistance. This work was funded by the National Institutes of Health (grants T32-HL007088 to D.A.R.-G. and CA162086 and CA101937 to T.J.L.) and the Barnes Jewish Hospital Foundation (to T.J.L.). The Washington University Proteomics Core is supported by grants from the National Institute of General Medical Sciences (8 P41 GM103422-35), the National Cancer Institute (P30 CA091842), and the National Center for Advancing Translational Sciences (UL1 TR000448).
PY - 2014/4/14
Y1 - 2014/4/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84898545028&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2014.02.010
DO - 10.1016/j.ccr.2014.02.010
M3 - Article
C2 - 24656771
AN - SCOPUS:84898545028
SN - 1535-6108
VL - 25
SP - 442
EP - 454
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -