Abstract
The Epstein-Barr virus (EBV) is present in the tumour cells of a subset of patients with classic Hodgkin lymphoma (cHL), yet the contribution of the virus to the pathogenesis of these tumours remains only poorly understood. The EBV genome in virus-associated cHL expresses a limited subset of genes, restricted to the non-coding Epstein-Barr virus-encoded RNAs (EBERs) and viral miRNA, as well as only three virus proteins; the Epstein-Barr virus nuclear antigen-1 (EBNA1), and the two latent membrane proteins, known as LMP1 and LMP2, the latter of which has two isoforms, LMP2A and LMP2B. LMP1 and LMP2A are of particular interest because they are co-expressed in tumour cells and can activate cellular signalling pathways, driving aberrant cellular transcription in infected B cells to promote lymphomagenesis. This article seeks to bring together the results of recent studies of the latent membrane proteins in different B cell systems, including experiments in animal models as well as a re-analysis of our own transcriptional data. In doing so, we summarise the potentially co-operative and antagonistic effects of the LMPs that are relevant to B cell lymphomagenesis.
Highlights
The Epstein-Barr virus (EBV) genome in Hodgkin/Reed Sternberg (HRS) cells, for example, expresses a restricted pattern of virus latency, known as latency II, characterised by the presence of Epstein-Barr virus nuclear antigen-1 (EBNA1), the two latent membrane proteins LMP1 and LMP2, the Epstein Barr encoded RNAs (EBERs), and the viral miRNA [64,65,66]
Using primary human germinal centre (GC) B cells as a model, we showed that LMP1 alone could recapitulate almost one-quarter of the transcriptional changes observed in classic Hodgkin lymphoma (cHL) cells, including the characteristic loss of B cell identity [87]
It is noteworthy that this study showed that LMP1 and LMP2A both enhanced the viability of transgenic B cells when expressed singly, yet surprisingly, B cells co-expressing LMP1 and LMP2A had a viability that was similar to littermate controls [113]
Summary
The Epstein-Barr virus (EBV) is associated with the pathogenesis of several types of B cell non-Hodgkin lymphoma (NHL; Burkitt lymphoma, diffuse large B cell lymphoma) as well as cases of classic Hodgkin lymphoma (cHL). These two major subgroups of B cell lymphoma are diagnosed on the basis of histopathological differences. Cytokines which can induce JAK/STAT activation are produced either by the HRS cells or by cells of the tumour microenvironment This in turn leads to increased levels of phosphorylated forms of STAT3, STAT5, and STAT6 [32,33,34]. The specific nature of the defects in EBV-specific immunity that predispose individuals to an increased risk of EBV-positive cHL have yet to be identified
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