Dnmt3b is a haploinsufficient tumor suppressor gene in Myc-induced lymphomagenesis

Aparna Vasanthakumar, Janet B. Lepore, Matthew H. Zegarek, Masha Kocherginsky, Mahi Singh, Elizabeth M. Davis, Petra A. Link, John Anastasi, Michelle M. Le Beau, Adam R. Karpf, Lucy A. Godley*

*Corresponding author for this work

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

The drivers of abnormal DNA methylation in human cancers include widespread aberrant splicing of the DNMT3B gene, producing abnormal transcripts that encode truncated proteins that may act as dominant negative isoforms. To test whether reduced Dnmt3b dosage can alter tumorigenesis, we bred Dnmt3b+/- mice to Em-Myc mice, a mouse model susceptible to B-cell lymphomas. Em-Myc/Dnmt3b+/- mice showed a dramatic acceleration of lymphomagenesis, greater even than that observed in Em-Myc mice that express a truncated DNMT3B isoform found in human tumors, DNMT3B7. This finding indicates that Dnmt3b can act as a haploinsufficient tumor suppressor gene. Although reduction in both Dnmt3b dosage and expression of DNMT3B7 within the Em-Myc system had similar effects on tumorigenesis and DNA hypermethylation, different molecular mechanisms appear to underlie these changes. This study offers insight into how de novo DNA methyltransferases function as tumor suppressors and the sensitivity of Myc-induced lymphomas to DNA methylation.

Original languageEnglish (US)
Pages (from-to)2059-2063
Number of pages5
JournalBlood
Volume121
Issue number11
DOIs
StatePublished - Jan 1 2013

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Vasanthakumar, A., Lepore, J. B., Zegarek, M. H., Kocherginsky, M., Singh, M., Davis, E. M., Link, P. A., Anastasi, J., Le Beau, M. M., Karpf, A. R., & Godley, L. A. (2013). Dnmt3b is a haploinsufficient tumor suppressor gene in Myc-induced lymphomagenesis. Blood, 121(11), 2059-2063. https://doi.org/10.1182/blood-2012-04-421065