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

doi:10.1016/j.celrep.2016.04.004

Cell Reports (May 2016)

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

DOI: https://doi.org/10.1016/j.celrep.2016.04.004
Journal volume & issue: Vol. 15, no. 6
pp. 1190 – 1201

Abstract

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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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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