DNMT3B overexpression contributes to aberrant DNA methylation and MYC-driven tumor maintenance in T-ALL and Burkitt's lymphoma

Candace J. Poole, Wenli Zheng, Atul Lodh, Aleksey Yevtodiyenko, Daniel Liefwalker, Honglin Li, Dean W. Felsher, Jan van Riggelen

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Aberrant DNA methylation is a hallmark of cancer. However, our understanding of how tumor cell-specific DNA methylation patterns are established and maintained is limited. Here, we report that in T-cell acute lymphoblastic leukemia (T-ALL) and Burkitt's lymphoma the MYC oncogene causes overexpression of DNA methyltransferase (DNMT) 1 and 3B, which contributes to tumor maintenance. By utilizing a tetracycline-regulated MYC transgene in a mouse T-ALL (EμSRa-tTA;tet-o- MYC) and human Burkitt's lymphoma (P493-6) model, we demonstrated that DNMT1 and DNMT3B expression depend on high MYC levels, and that their transcription decreased upon MYC-inactivation. Chromatin immunoprecipitation indicated that MYC binds to the DNMT1 and DNMT3B promoters, implicating a direct transcriptional regulation. Hence, shRNA-mediated knock-down of endogenous MYC in human T-ALL and Burkitt's lymphoma cell lines, downregulated DNMT3B expression. Knock-down and pharmacologic inhibition of DNMT3B in T-ALL reduced cell proliferation associated with genome-wide changes in DNA methylation, indicating a tumor promoter function during tumor maintenance. We provide novel evidence that MYC directly deregulates the expression of both de novo and maintenance DNMTs, showing that MYC controls DNA methylation in a genome-wide fashion. Our finding that a coordinated interplay between the components of the DNA methylating machinery contributes to MYCdriven tumor maintenance highlights the potential of specific DNMTs for targeted therapies.

Original languageEnglish (US)
Pages (from-to)76898-76920
Number of pages23
JournalOncotarget
Volume8
Issue number44
DOIs
StatePublished - 2017

Keywords

  • DNA methylation
  • DNMT3B
  • Leukemia/lymphoma
  • MYC

ASJC Scopus subject areas

  • Oncology

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    Poole, C. J., Zheng, W., Lodh, A., Yevtodiyenko, A., Liefwalker, D., Li, H., Felsher, D. W., & van Riggelen, J. (2017). DNMT3B overexpression contributes to aberrant DNA methylation and MYC-driven tumor maintenance in T-ALL and Burkitt's lymphoma. Oncotarget, 8(44), 76898-76920. https://doi.org/10.18632/oncotarget.20176