Work

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

Year: 2017

Type: article

Abstract: // Candace J. Poole 1, * , Wenli Zheng 1, * , Atul Lodh 1 , Aleksey Yevtodiyenko 2 , Daniel Liefwalker 2 , Honglin Li 1 , Dean W. Felsher 2 and Jan van Riggelen 1 1 Augusta University, Department of Biochemistry and Molecular Biology, Augusta, GA 30912, USA 2 Stanford University School of Medicine, Division of Oncology, Departments of Medicine and Pathology, Stanford, CA 94305, USA * These authors have contributed equally to this work Correspondence to: 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 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 (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.

Source: Oncotarget

DOI: 10.18632/oncotarget.20176