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

Oncotarget
Candace J PooleJan van Riggelen

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, sh...Continue Reading

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Citations

May 21, 2019·Biomarker Insights·Kah Keng WongTina M Green
Sep 12, 2019·Frontiers in Genetics·Xiaoyuan LinLuc Peelman
Nov 21, 2018·Cancers·Candace J PooleJan van Riggelen
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Nov 25, 2020·Blood Reviews·Alain CheblyEdith Chevret
Aug 14, 2021·Blood Reviews·Ting YangYun Dai
Jan 23, 2022·Human Cell·Saran Chattopadhyaya, Somnath Ghosal

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Datasets Mentioned

BETA
GSE101907

Methods Mentioned

BETA
acetylation
transgenic
immunoprecipitation
ChIP
ChIP-chip
ChIP-seq
RNA-seq
Illumina sequencing
RRBS
dissect

Software Mentioned

JASPAR
UCSC Genome Browser
Oncomine
Trim Galore !
bismark
FastQC
ImageJ
methylKit

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