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

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...

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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
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cites cdi_FETCH-LOGICAL-c715t-f0b8b26d2734f0bc85c1bb8514b785ef3d2923f4b157c9b0afc1281fb56eaf453
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container_issue 43
container_start_page 5436
container_title Oncogene
container_volume 34
creator Haney, S L
Hlady, R A
Opavska, J
Klinkebiel, D
Pirruccello, S J
Dutta, S
Datta, K
Simpson, M A
Wu, L
Opavsky, R
description 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.
doi_str_mv 10.1038/onc.2014.472
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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. 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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. 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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. 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identifier ISSN: 0950-9232
ispartof Oncogene, 2015-10, Vol.34 (43), p.5436-5446
issn 0950-9232
1476-5594
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4533871
source Springer Nature
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
title Methylation-independent repression of Dnmt3b contributes to oncogenic activity of Dnmt3a in mouse MYC-induced T-cell lymphomagenesis
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