title: CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression.
abstract: DNMT3A mutations occur in ∼25% of acute myeloid leukemia (AML) patients. The most common mutation, DNMT3AR882H, has dominant negative activity that reduces DNA methylation activity by ∼80% in vitro. To understand the contribution of DNMT3A-dependent methylation to leukemogenesis, we performed whole-genome bisulfite sequencing of primary leukemic and non-leukemic cells in patients with or without DNMT3AR882mutations. Non-leukemic hematopoietic cells with DNMT3AR882Hdisplayed focal methylation loss, suggesting that hypomethylation antedates AML. Although virtually all AMLs with wild-type DNMT3A displayed CpG island hypermethylation, this change was not associated with gene silencing and was essentially absent in AMLs with DNMT3AR882mutations. Primary hematopoietic stem cells expanded with cytokines were hypermethylated in a DNMT3A-dependent manner, suggesting that hypermethylation may be a response to, rather than a cause of, cellular proliferation. Our findings suggest that hypomethylation is an initiating phenotype in AMLs with DNMT3AR882, while DNMT3A-dependent CpG island hypermethylation is a consequence of AML progression.
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; The McDonnell Genome Institute, 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 School of Medicine, St. Louis, MO 63110, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Russler-Germain
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Shamika
authors.initials: S
authors.lastname: Ketkar
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Nichole M
authors.initials: NM
authors.lastname: Helton
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Lamprecht
authors.affiliation: The McDonnell Genome Institute, Washington University, St. Louis, MO 63110, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.affiliation: The McDonnell Genome Institute, Washington University, St. Louis, MO 63110, USA.
authors.forename: Catrina C
authors.initials: CC
authors.lastname: Fronick
authors.affiliation: The McDonnell Genome Institute, Washington University, St. Louis, MO 63110, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: O'Laughlin
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Heath
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Marwan
authors.initials: M
authors.lastname: Shinawi
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Westervelt
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Payton
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; The McDonnell Genome Institute, Washington University, St. Louis, MO 63110, USA.
authors.forename: Lukas D
authors.initials: LD
authors.lastname: Wartman
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Welch
authors.affiliation: The McDonnell Genome Institute, 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 School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walter
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; The McDonnell Genome Institute, Washington University, St. Louis, MO 63110, USA. Electronic address: timley@wustl.edu.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
mesh_terms: D001854:Bone Marrow Cells / Q000473:pathology; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D017422:Sequence Analysis, DNA
chemical_list: C000717967:DNMT3A protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: AML; CpG island hypermethylation; DNA methylation; DNMT3A; leukemia