Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a
Staci L. Haney,
G. Michael Upchurch,
Jana Opavska,
David Klinkebiel,
Ryan A. Hlady,
Abhinav Suresh,
Samuel J. Pirruccello,
Vipul Shukla,
Runqing Lu,
Stefan Costinean,
Angie Rizzino,
Adam R. Karpf,
Shantaram Joshi,
Patrick Swanson,
Rene Opavsky
Affiliations
Staci L. Haney
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
G. Michael Upchurch
Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
Jana Opavska
Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
David Klinkebiel
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
Ryan A. Hlady
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
Abhinav Suresh
Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
Samuel J. Pirruccello
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
Vipul Shukla
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
Runqing Lu
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
Stefan Costinean
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
Angie Rizzino
Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
Adam R. Karpf
Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
Shantaram Joshi
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
Patrick Swanson
Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68102, USA
Rene Opavsky
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
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 Dnmt3aΔ/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 Dnmt3aΔ/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.
