title: Epimutations mimic genomic mutations of DNMT3A in acute myeloid leukemia.
abstract: Mutations in the genetic sequence of the DNA de novo methyltransferase DNMT3A (DNA methyltransferase 3A) are found in many patients with acute myeloid leukemia (AML). They lead to dysfunction of DNMT3A protein and represent a marker for poor prognosis. Effects of genetic mutations can be mimicked by epigenetic modifications in the DNA methylation (DNAm) pattern. Using DNAm profiles of the Cancer Genome Atlas Research Network (TCGA), we identified aberrant hypermethylation at an internal promoter region of DNMT3A, which occurred in about 40% of AML patients. Bisulfite pyrosequencing assays designed for this genomic region validated hypermethylation specifically in a subset of our AML samples. High DNAm levels at this site are particularly observed in samples without genetic mutations in DNMT3A. Epimutations and mutations of DNMT3A were associated with related gene expression changes such as upregulation of the homeobox genes in HOXA and HOXB clusters. Furthermore, epimutations in DNMT3A were enriched in patients with poor or intermediate cytogenetic risk, and in patients with shorter event-free survival and overall survival (OS). Taken together, aberrant DNA hypermethylation within the DNMT3A gene, in analogy to DNMT3A mutations, is frequently observed in AML and both modifications seem to be useful for risk stratification or choice of therapeutic regimen.
authors.affiliation: Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Jost
authors.affiliation: Institute for Biomedical Engineering-Cell Biology, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: Q
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: C I
authors.initials: CI
authors.lastname: Weidner
authors.affiliation: Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Wilop
authors.affiliation: Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Walenda
authors.affiliation: Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schemionek
authors.affiliation: Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Herrmann
authors.affiliation: Institute for Biomedical Engineering-Cell Biology, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Zenke
authors.affiliation: Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: T H
authors.initials: TH
authors.lastname: Brümmendorf
authors.affiliation: Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Koschmieder
authors.affiliation: Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Wagner
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic / Q000235:genetics*; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; C000717967:DNMT3A protein, human; D012333:RNA, Messenger; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A