DNMT3B overexpression contributes to aberrant DNA methylation and MYC-driven tumor maintenance in T-ALL and Burkitt’s lymphoma
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Candace J. Poole1,*, Wenli Zheng1,*, Atul Lodh1, Aleksey Yevtodiyenko2, Daniel Liefwalker2, Honglin Li1, Dean W. Felsher2 and Jan van Riggelen1
1Augusta University, Department of Biochemistry and Molecular Biology, Augusta, GA 30912, USA
2Stanford University School of Medicine, Division of Oncology, Departments of Medicine and Pathology, Stanford, CA 94305, USA
*These authors have contributed equally to this work
Jan van Riggelen, email: [email protected]
Keywords: MYC, DNMT3B, DNA methylation, leukemia/lymphoma
Received: January 13, 2017 Accepted: July 18, 2017 Published: August 10, 2017
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 (EμSRα-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 MYC-driven tumor maintenance highlights the potential of specific DNMTs for targeted therapies.
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