title: The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers.
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.
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Russler-Germain
authors.affiliation: Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Spencer
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Young
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Lamprecht
authors.affiliation: The Genome Institute, Washington University, St. Louis, MO 63110, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Miller
authors.affiliation: The Genome Institute, Washington University, St. Louis, MO 63110, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Fulton
authors.affiliation: Division of Metabolism, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Meyer
authors.affiliation: Division of Metabolism, Department of Medicine, Washington University, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA.
authors.forename: Petra
authors.initials: P
authors.lastname: Erdmann-Gilmore
authors.affiliation: Division of Metabolism, Department of Medicine, Washington University, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA.
authors.forename: R Reid
authors.initials: RR
authors.lastname: Townsend
authors.affiliation: The Genome Institute, Washington University, St. Louis, MO 63110, USA; Department of Genetics, Washington University, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA; The Genome Institute, Washington University, St. Louis, MO 63110, USA; Department of Genetics, Washington University, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA. Electronic address: timley@wustl.edu.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry / Q000235:genetics*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011379:Prognosis; D011487:Protein Conformation
chemical_list: C000717967:DNMT3A protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A