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

S. L. Haney, R. A. Hlady, J. Opavska, David L Klinkebiel, Samuel Jay Pirruccello, S. Dutta, Kaustubh Datta, M. A. Simpson, L. Wu, R. Opavsky

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5436-5446
Number of pages11
JournalOncogene
Volume34
Issue number43
DOIs
StatePublished - Oct 1 2015

Fingerprint

Methylation
Lymphoma
T-Lymphocytes
Up-Regulation
Tumor Suppressor Genes
Disease Progression
T-Cell Leukemia
T-Cell Lymphoma
Cytosine
DNA
Methyltransferases
Gene Expression Profiling
Genes
Carcinogenesis
Cell Proliferation
Mutation
Neoplasms
DNA methyltransferase 3A

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Methylation-independent repression of Dnmt3b contributes to oncogenic activity of Dnmt3a in mouse MYC-induced T-cell lymphomagenesis. / Haney, S. L.; Hlady, R. A.; Opavska, J.; Klinkebiel, David L; Pirruccello, Samuel Jay; Dutta, S.; Datta, Kaustubh; Simpson, M. A.; Wu, L.; Opavsky, R.

In: Oncogene, Vol. 34, No. 43, 01.10.2015, p. 5436-5446.

Research output: Contribution to journalArticle

Haney, S. L. ; Hlady, R. A. ; Opavska, J. ; Klinkebiel, David L ; Pirruccello, Samuel Jay ; Dutta, S. ; Datta, Kaustubh ; Simpson, M. A. ; Wu, L. ; Opavsky, R. / Methylation-independent repression of Dnmt3b contributes to oncogenic activity of Dnmt3a in mouse MYC-induced T-cell lymphomagenesis. In: Oncogene. 2015 ; Vol. 34, No. 43. pp. 5436-5446.
@article{f441af7fefc64013ae9a2a74209e11ed,
title = "Methylation-independent repression of Dnmt3b contributes to oncogenic activity of Dnmt3a in mouse MYC-induced T-cell lymphomagenesis",
abstract = "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.",
author = "Haney, {S. L.} and Hlady, {R. A.} and J. Opavska and Klinkebiel, {David L} and Pirruccello, {Samuel Jay} and S. Dutta and Kaustubh Datta and Simpson, {M. A.} and L. Wu and R. Opavsky",
year = "2015",
month = "10",
day = "1",
doi = "10.1038/onc.2014.472",
language = "English (US)",
volume = "34",
pages = "5436--5446",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "43",

}

TY - JOUR

T1 - Methylation-independent repression of Dnmt3b contributes to oncogenic activity of Dnmt3a in mouse MYC-induced T-cell lymphomagenesis

AU - Haney, S. L.

AU - Hlady, R. A.

AU - Opavska, J.

AU - Klinkebiel, David L

AU - Pirruccello, Samuel Jay

AU - Dutta, S.

AU - Datta, Kaustubh

AU - Simpson, M. A.

AU - Wu, L.

AU - Opavsky, R.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84945460545&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84945460545&partnerID=8YFLogxK

U2 - 10.1038/onc.2014.472

DO - 10.1038/onc.2014.472

M3 - Article

C2 - 25639876

AN - SCOPUS:84945460545

VL - 34

SP - 5436

EP - 5446

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 43

ER -