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 more efficient targeted therapeutic strategies.
Highlights
The underlying causes of an active B lymphocyte malignant transformation are attributable to events such as infections or environmental carcinogen exposures that, by interfering with the physiological cell differentiation process within secondary lymphoid organs, predispose the cell to a multistep pathogenic cascade resulting in cancer-related gene deregulation and subsequent lymphoma development [1,2]
The resulting heatmap, which illustrates a methylome pattern capable of discriminating samples according to their cell transformation status, highlights DNA methylation changes associated with the Epstein–Barr virus (EBV)-positive lymphoma condition (Figure 1a)
Since Aflatoxin B1 (AFB1) is associated with eBL, we further investigated any common differentially methylated positions (DMPs) with infection status by integrating publicly available data referring to white blood cell samples from a Gambian population heavily exposed to AFB1 (Figure 1b)
Summary
The underlying causes of an active B lymphocyte malignant transformation are attributable to events such as infections or environmental carcinogen exposures that, by interfering with the physiological cell differentiation process within secondary lymphoid organs, predispose the cell to a multistep pathogenic cascade resulting in cancer-related gene deregulation and subsequent lymphoma development [1,2]. This occurs in advanced Burkitt lymphoma (latency 1 program), which progressively becomes virus-independent, likely maintained by infection-induced epigenetic changes according to a “hit and run” oncogenesis mechanism, consistent with the absence of expression of key EBV oncoproteins, including LMP1 [26,27] In this respect, EBV is already known to exploit the host’s epigenetic machinery to Cancers 2022, 14, 1284 modify both its chromatin organization and DNA methylation, and this interplay between viral factors and human epigenetic regulators inevitably affects the host epigenetic landscape as well, further contributing to the oncogenic hijacking of the maturation pathways of the infected B cell [28–30]. Any significant change in the developing epigenome of the infant is likely to predispose the child to increased disease susceptibility, especially in the presence of a proliferative stimulus provided by EBV infection [42,43]
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