Loss of Dnmt3a induces CLL and PTCL with distinct methylomes and transcriptomes in mice

Staci L Haney; Garland M Upchurch; Jana Opavska; David Klinkebiel; Adams Kusi Appiah; Lynette M Smith; Tayla B Heavican; Javeed Iqbal; Shantaram Joshi; Rene Opavsky

doi:10.1038/srep34222

Loss of Dnmt3a induces CLL and PTCL with distinct methylomes and transcriptomes in mice

Sci Rep. 2016 Sep 28:6:34222. doi: 10.1038/srep34222.

Authors

Staci L Haney¹, Garland M Upchurch², Jana Opavska², David Klinkebiel³, Adams Kusi Appiah⁴, Lynette M Smith⁴, Tayla B Heavican⁵, Javeed Iqbal^{5

6}, Shantaram Joshi^{1

6}, Rene Opavsky^{1

2

6}

Affiliations

¹ Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA.
² Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA.
³ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA.
⁴ College of Public Health, UNMC, Omaha, Nebraska, 68198, USA.
⁵ Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA.
⁶ Center for Leukemia and Lymphoma Research, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA.

Abstract

Cytosine methylation of DNA is an epigenetic modification involved in the repression of genes that affect biological processes including hematopoiesis. It is catalyzed by DNA methyltransferases, one of which -DNMT3A- is frequently mutated in human hematologic malignancies. We have previously reported that Dnmt3a inactivation in hematopoietic stem cells results in chronic lymphocytic leukemia (CLL) and CD8-positive peripheral T cell lymphomas (PTCL) in EμSRα-tTA;Teto-Cre;Dnmt3a^fl/fl; Rosa26LOXP^EGFP/EGFP (Dnmt3a^Δ/Δ) mice. The extent to which molecular changes overlap between these diseases is not clear. Using high resolution global methylation and expression analysis we show that whereas patterns of methylation and transcription in normal B-1a cells and CD8-positive T cells are similar, methylomes and transcriptomes in malignant B-1a and CD8+ T cells are remarkably distinct, suggesting a cell-type specific function for Dnmt3a in cellular transformation. Promoter hypomethylation in tumors was 10 times more frequent than hypermethylation, three times more frequent in CLL than PTCL and correlated better with gene expression than hypermethylation. Cross-species molecular comparison of mouse and human CLL and PTCL reveals significant overlaps and identifies putative oncogenic drivers of disease. Thus, Dnmt3a^Δ/Δ mice can serve as a new mouse model to study CLL and PTCL in relevant physiological settings.

Abstract

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