Burkitt Lymphomas Evolve to Escape Dependencies on Epstein-Barr Virus

Abstract

Epstein-Barr Virus (EBV) can transform B cells and contributes to the development of Burkitt lymphoma and other cancers. Through decades of study, we now recognize that many of the viral genes required to transform cells are not expressed in EBV-positive Burkitt lymphoma (BL) tumors, likely due to the immune pressure exerted on infected cells. This recognition has led to the hypothesis that the loss of expression of these viral genes must be compensated through some mechanisms. Recent progress in genome-wide mutational analysis of tumors provides a wealth of data about the cellular mutations found in EBV-positive BLs. Here, we review common cellular mutations found in these tumors and consider how they may compensate for the viral genes that are no longer expressed. Understanding these mutations and how they may substitute for EBV's genes and contribute to lymphomagenesis can serve as a launchpad for more mechanistic studies, which will help us navigate the sea of genomic data available today, and direct the discoveries necessary to improve the treatment of EBV-positive BLs.

Keywords: B cell; Burkitt lymphoma; Epstein–Barr virus; cellular mutations; compensation; next-generation sequencing; tumor evolution.

Figure 1

A model for EBV-positive Burkitt lymphomagenesis. Cells transformed with EBV are provided with oncogenic advantages including the ability to proliferate and the ability to avoid apoptosis through the expression of viral transforming genes. However, EBV infected cells are targeted by the host’s immune system. As mutations randomly accumulate in cells, they allow expression of some of EBV’s genes to be turned off if compensated by such cellular mutations and reduce immune-mediated tumor cell killing.

Figure 2

A map of the latent EBV genome. The 165 kilobase pair double-stranded DNA genome exists as a plasmid maintained within the nucleus of infected cells. The origin of plasmid replication (oriP) is shown in yellow. The thin lines represent transcripts, each color representing the promoter that drives their transcription, C (green), W (purple), and Q (orange). The black boxed arrows represent the approximate locations of exons encoding latent proteins. The black triangles at the top represent the highly transcribed non-coding RNA EBERs, and the red triangles represent the two sets of miRNAs.

Figure 3

Comparing mutation loads for select genes in Wp-restricted (blue bars) and canonical (yellow bars) Burkitt lymphoma tumors. Data are derived from publicly available datasets (Grande et al., 2019). Tumors were designated EBV-positive based on detectable levels of EBNA1. EBV-positive tumors were categorized as Wp-restricted if EBNA2 expression was absent and EBNA3A/EBNA3C expression detected.