Methylation-independent repression of Dnmt3b contributes to oncogenic activity of Dnmt3a in mouse MYC-induced T-cell lymphomagenesis

• Published in: Oncogene 2015-10, Vol.34 (43), p.5436-5446
• Main Authors: Haney, S L, Hlady, R A, Opavska, J, Klinkebiel, D, Pirruccello, S J, Dutta, S, Datta, K, Simpson, M A, Wu, L, Opavsky, R
• Format: Article
• Language: English
• Subjects: 13/31; 13/44; 38/39; 38/61; 631/67/1990/291/1621/1916; 64/110; 64/60; Analysis; Animals; Apoptosis; Carcinogenesis - genetics; Cell Biology; Cell Proliferation - genetics; Cells; Cytosine; Deoxyribonucleic acid; Disease Models, Animal; Disease Progression; DNA; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA - genetics; DNA methylation; DNA Methylation - genetics; DNA methyltransferase; DNA Methyltransferase 3A; DNA Methyltransferase 3B; Gene expression; Genes; Genetic aspects; Genetic transformation; Human Genetics; Internal Medicine; Leukemia; Lymphocytes T; Lymphoma; Lymphoma, T-Cell - genetics; Lymphoma, T-Cell - pathology; Medicine; Medicine & Public Health; Methylation; Methyltransferases; Mice; Myc protein; Non-Hodgkin's lymphomas; Oncology; original-article; Physiological aspects; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins c-myc - genetics; Risk factors; Rodents; T cells; T-cell lymphoma; Tetracycline; Tetracyclines; Transcriptome - genetics; Tumor suppressor genes; Tumorigenesis; Up-Regulation - genetics
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.472

DNA methyltransferase 3A (DNMT3A) catalyzes cytosine methylation of mammalian genomic DNA. In addition to myeloid malignancies, mutations in DNMT3A have been recently reported in T-cell lymphoma and leukemia, implying a possible involvement in the pathogenesis of human diseases. However, the role of Dnmt3a in T-cell transformation in vivo is poorly understood. Here we analyzed the functional consequences of Dnmt3a inactivation in a mouse model of MYC-induced T-cell lymphomagenesis (MTCL). Loss of Dnmt3a delayed tumorigenesis by suppressing cellular proliferation during disease progression. Gene expression profiling and pathway analysis identified upregulation of 17 putative tumor suppressor genes, including DNA methyltransferase Dnmt3b, in Dnmt3a-deficient lymphomas as molecular events potentially responsible for the delayed lymphomagenesis in Dnmt3a Δ/Δ mice. Interestingly, promoter and gene body methylation of these genes was not substantially changed between control and Dnmt3a-deficient lymphomas, suggesting that Dnmt3a may inhibit their expression in a methylation-independent manner. Re-expression of both wild type and catalytically inactive Dnmt3a in Dnmt3a Δ/Δ lymphoma cells in vitro inhibited Dnmt3b expression, indicating that Dnmt3b upregulation may be directly repressed by Dnmt3a. Importantly, genetic inactivation of Dnmt3b accelerated lymphomagenesis in Dnmt3a Δ/Δ mice, demonstrating that upregulation of Dnmt3b is a relevant molecular change in Dnmt3a-deficient lymphomas that inhibits disease progression. Collectively, our data demonstrate an unexpected oncogenic role for Dnmt3a in MTCL through methylation-independent repression of Dnmt3b and possibly other tumor suppressor genes.