title: Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a.
abstract: DNA methyltransferase 3a (DNMT3A) catalyzes the formation of 5-methyl-cytosine in mammalian genomic DNA, and it is frequently mutated in human hematologic malignancies. Bi-allelic loss of Dnmt3a in mice results in leukemia and lymphoma, including chronic lymphocytic leukemia (CLL). Here, we investigate whether mono-allelic loss of Dnmt3a is sufficient to induce disease. We show that, by 16 months of age, 65% of Dnmt3a(+/-) mice develop a CLL-like disease, and 15% of mice develop non-malignant myeloproliferation. Genome-wide methylation analysis reveals that reduced Dnmt3a levels induce promoter hypomethylation at similar loci in Dnmt3a(+/-) and Dnmt3a(Δ/Δ) CLL, suggesting that promoters are particularly sensitive to Dnmt3a levels. Gene expression analysis identified 26 hypomethylated and overexpressed genes common to both Dnmt3a(+/-) and Dnmt3a(Δ/Δ) CLL as putative oncogenic drivers. Our data provide evidence that Dnmt3a is a haplo-insufficient tumor suppressor in CLL and highlights the importance of deregulated molecular events in disease pathogenesis.
authors.affiliation: Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Staci L
authors.initials: SL
authors.lastname: Haney
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: G Michael
authors.initials: GM
authors.lastname: Upchurch
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Opavska
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: David
authors.initials: D
authors.lastname: Klinkebiel
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Hlady
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Suresh
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Center for Leukemia and Lymphoma Research, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Pirruccello
authors.affiliation: Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Vipul
authors.initials: V
authors.lastname: Shukla
authors.affiliation: Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Runqing
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Costinean
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Angie
authors.initials: A
authors.lastname: Rizzino
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Karpf
authors.affiliation: Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA; Center for Leukemia and Lymphoma Research, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Shantaram
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68102, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Swanson
authors.affiliation: Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; Center for Leukemia and Lymphoma Research, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: ropavsky@unmc.edu.
authors.forename: Rene
authors.initials: R
authors.lastname: Opavsky
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D015973:Gene Expression Regulation, Leukemic; D006579:Heterozygote; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000235:genetics*; D051379:Mice; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D059467:Transcriptome / Q000235:genetics
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A