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

Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a

Cell Rep. 2016 May 10;15(6):1190-201. doi: 10.1016/j.celrep.2016.04.004. Epub 2016 Apr 28.

Authors

Affiliations

¹ Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
² Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
³ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁴ Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
⁵ 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.
⁶ Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁷ 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.
⁸ 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.
⁹ Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68102, USA.
¹⁰ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Proliferation
DNA (Cytosine-5-)-Methyltransferases / deficiency
DNA (Cytosine-5-)-Methyltransferases / metabolism*
DNA Methylation / genetics*
DNA Methyltransferase 3A
Gene Expression Regulation, Leukemic*
Heterozygote
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / enzymology*
Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
Mice
Promoter Regions, Genetic*
Transcription, Genetic
Transcriptome / genetics

Substances

DNMT3A protein, human
Dnmt3a protein, mouse
DNA (Cytosine-5-)-Methyltransferases
DNA Methyltransferase 3A

Abstract

Publication types

MeSH terms

Substances

Grants and funding