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Epigenetic alteration of the cancer-related gene TGFBI in B cells infected with Epstein–Barr virus and exposed to aflatoxin B1: potential role in Burkitt lymphoma development
Date
2022
Abstract
Burkitt lymphoma (BL) is a malignant B cell neoplasm that accounts for almost half of pediatric cancers in sub-Saharan African countries. Although the BL endemic prevalence is attributable to the combination of Epstein–Barr virus (EBV) infection with malaria and environmental carcinogens exposure, such as the food contaminant aflatoxin B1 (AFB1), the molecular determinants underlying the pathogenesis are not fully understood. Consistent with the role of epigenetic mechanisms at the interface between the genome and environment, AFB1 and EBV impact the methylome of respectively leukocytes and B cells specifically. Here, we conducted a thorough investigation of common epigenomic changes following EBV or AFB1 exposure in B cells. Genome-wide DNA methylation profiling identified an EBV–AFB1 common signature within the TGFBI locus, which encodes for a putative tumor suppressor often altered in cancer. Subsequent mechanistic analyses confirmed a DNA-methylation-dependent transcriptional silencing of TGFBI involving the recruitment of DNMT1 methyltransferase that is associated with an activation of the NF-κB pathway. Our results reveal a potential common mechanism of B cell transformation shared by the main risk factors of endemic BL (EBV and AFB1), suggesting a key determinant of disease that could allow the development of moreefficient targeted therapeutic strategies.
Supervisor
Description
Publisher
MDPI
Citation
Cancers, 2022, 14, 1284
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Mundo_2022_Epigenetic.pdf
Adobe PDF, 1.76 MB
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Funding Information
This research was funded by La Ligue Contre le Cancer (LNCC) Rhone (GR-IARC-2014-04-07-03 to R.A. and OPE-2017-0009 to H.G.), Oncostarter-(CLARA) (GR-IARC-2014-05-15-02 to R.A.), IARC Junior Award 2016 (AFEES-2016 to R.A.), Plan Cancer-INSERM (17CE032-00 to R.A.), FWO Belgium (G085921N, to Z.H. and R.A.), Fondation ARC pour la Recherche sur le Cancer (ARCDOC42021020003117 to F.M. (Francesca Manara)), MSCA-IF (VirGO 896422 to L.M.), Childrenwith Cancer UK (CwC UK, PP201910-33 to G.A.O.), Grand Challenges Exploration Grant from the Bill and Melinda Gates Foundation (Grant Number: OPP1061062 to Z.H.) and PEDIAC origines des cancers pédiatriques grant from the national cancer institute (INCA France; grant number: INCA_15670 to R.K. and Z.H.)