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

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

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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; Rosa26LOXPEGFP/EGFP (Dnmt3aδ/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, Dnmt3aδ/δ mice can serve as a new mouse model to study CLL and PTCL in relevant physiological settings.

Original languageEnglish (US)
Article number34222
JournalScientific reports
Volume6
DOIs
StatePublished - Sep 28 2016

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Peripheral T-Cell Lymphoma
B-Cell Chronic Lymphocytic Leukemia
Transcriptome
Methylation
T-Lymphocytes
Biological Phenomena
Cytosine
Hematopoiesis
Methyltransferases
Hematologic Neoplasms
DNA Methylation
Hematopoietic Stem Cells
Epigenomics
Gene Expression
DNA
Genes
Neoplasms

ASJC Scopus subject areas

  • General

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Loss of Dnmt3a induces CLL and PTCL with distinct methylomes and transcriptomes in mice. / Haney, Staci L.; Upchurch, Garland M.; Opavska, Jana; Klinkebiel, David L; Appiah, Adams Kusi; Smith, Lynette M; Heavican, Tayla B.; Iqbal, Javeed; Joshi, Shantaram S; Opavsky, Rene.

In: Scientific reports, Vol. 6, 34222, 28.09.2016.

Research output: Contribution to journalArticle

Haney, Staci L. ; Upchurch, Garland M. ; Opavska, Jana ; Klinkebiel, David L ; Appiah, Adams Kusi ; Smith, Lynette M ; Heavican, Tayla B. ; Iqbal, Javeed ; Joshi, Shantaram S ; Opavsky, Rene. / Loss of Dnmt3a induces CLL and PTCL with distinct methylomes and transcriptomes in mice. In: Scientific reports. 2016 ; Vol. 6.
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