Contribution of Epstein⁻Barr Virus Latent Proteins to the Pathogenesis of Classical Hodgkin Lymphoma

Pathogenic viruses have evolved to manipulate the host cell utilising a variety of strategies including expression of viral proteins to hijack or mimic the activity of cellular functions. DNA tumour viruses often establish latent infection in which no new virions are produced, characterized by the expression of a restricted repertoire of so-called latent viral genes. These latent genes serve to remodel cellular functions to ensure survival of the virus within host cells, often for the lifetime of the infected individual. However, under certain circumstances, virus infection may contribute to transformation of the host cell; this event is not a usual outcome of infection. Here, we review how the Epstein–Barr virus (EBV), the prototypic oncogenic human virus, modulates host cell functions, with a focus on the role of the EBV latent genes in classical Hodgkin lymphoma

The Oncogenic Lipid Sphingosine-1-Phosphate Impedes the Phagocytosis of Tumor Cells by M1 Macrophages in Diffuse Large B Cell Lymphoma

Background: A total of 30–40% of diffuse large B cell lymphoma (DLBCL) patients will either not respond to the standard therapy or their disease will recur. The first-line treatment for DLBCL is rituximab and combination chemotherapy. This treatment involves the chemotherapy-induced recruitment of tumor-associated macrophages that recognize and kill rituximab-opsonized DLBCL cells. However, we lack insights into the factors responsible for the recruitment and functionality of macrophages in DLBCL tumors. Methods: We have studied the effects of the immunomodulatory lipid sphingosine-1-phosphate (S1P) on macrophage activity in DLBCL, both in vitro and in animal models. Results: We show that tumor-derived S1P mediates the chemoattraction of both monocytes and macrophages in vitro and in animal models, an effect that is dependent upon the S1P receptor S1PR1. However, S1P inhibited M1 macrophage-mediated phagocytosis of DLBCL tumor cells opsonized with the CD20 monoclonal antibodies rituximab and ofatumumab, an effect that could be reversed by an S1PR1 inhibitor. Conclusions: Our data show that S1P signaling can modulate macrophage recruitment and tumor cell killing by anti-CD20 monoclonal antibodies in DLBCL. The administration of S1PR1 inhibitors could enhance the phagocytosis of tumor cells and improve outcomes for patients

Co-Expression of the Epstein-Barr Virus-Encoded Latent Membrane Proteins and the Pathogenesis of Classic Hodgkin Lymphoma

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

An investigation of the regulation of BLIMP1 by the epstein-barr virus in B cells

BLIMP1 is a transcription factor that regulates plasma cell differentiation. In this thesis I explore the regulation of BLIMP1 by EBV and by the EBV oncogene, latent membrane protein-1 (LMP1). In chapter 3, I show that BLIMP1α is down-regulated following the infection of germinal centre (GC) B cells with EBV. I also show that the ectopic expression of LMP1, was sufficient to decrease BLIMP1α expression in these cells and was accompanied by a partial disruption of the BLIMP1α transcriptional programme, including the aberrant induction of C-MYC. In chapter 4, I show that the ectopic expression of BLIMP1α in EBV-transformed cells and in EBV-positive Burkitt’s lymphoma cells can induce the viral lytic cycle. Chapter 5 provides evidence that LMP1 drives a reciprocal regulatory loop in GC B cells involving BLIMP1α and C-MYC which ultimately leads to the activation of C-MYC and the repression of BLIMP1α. Finally, in chapter 6, I present preliminary evidence showing that the BLIMP1β isoform is up-regulated in EBV-transformed B cells and in Hodgkin’s lymphoma cells; an effect which appeared to be mediated by hypomethylation of the BLIMP1β specific promoter. In summary, my results suggest that EBV can subvert normal B cell differentiation by modulating expression of the different BLIMP1 isoforms. These effects appear to be important not only for the regulation of the viral lytic cycle in B cells, but also potentially for the block in differentiation characteristic of EBV-associated B cell lymphomas

The contribution of ebv to the pathogenesis of classical hodgkin lymphoma

Hodgkin lymphoma (HL) exists in two major forms, the so-called classical type (cHL) and the nodular lymphocyte predominant type (NLPHL). Since NLPHL is considered to be an EBV-negative entity, this review focusses only on the cHL form. Although cHL is a curable disease in many cases, we still lack an understanding of its pathogenesis that could lead to kinder treatments for patients, and also to more effective therapies for the smaller subset of patients who are destined to die of their disease. One approach might be to therapeutically target the Epstein-Barr virus (EBV), which is present in up to one-half of cases in resource rich nations, and in almost all cases in some resource-poor countries. However, it has been suggested that EBV might be simply a silent passenger in cHL. In this review, we present evidence in support of a crucial role for EBV in virus-positive cHL. In particular, we highlight important epidemiological differences between EBV-positive and EBV-negative cHL that suggest different aetiologies, as well as genetic differences, including a different profile of somatic mutations pointing to a distinct contribution for EBV in substituting for cellular genetic changes that are required for disease development when the virus is absent. We also focus attention on important roles for the individual latent virus genes in the pathogenesis of cHL. Overall, this review suggests that a better understanding of how EBV contributes to the pathogenesis of cHL may eventually lead to improved stratification of patients and to the development of therapies that specifically target EBV or its latent genes.</p

Anmerkung zur Entscheidung der griechischen Wettbewerbskommission vom 14.7.2003

Since the discovery in 1964 of the Epstein-Barr virus (EBV) in African Burkitt lymphoma, this virus has been associated with a remarkably diverse range of cancer types. Because EBV persists in the B cells of the asymptomatic host, it can easily be envisaged how it contributes to the development of B-cell lymphomas. However, EBV is also found in other cancers, including T-cell/natural killer cell lymphomas and several epithelial malignancies. Explaining the aetiological role of EBV is challenging, partly because the virus probably contributes differently to each tumour and partly because the available disease models cannot adequately recapitulate the subtle variations in the virus-host balance that exist between the different EBV-associated cancers. A further challenge is to identify the co-factors involved; because most persistently infected individuals will never develop an EBV-associated cancer, the virus cannot be working alone. This article will review what is known about the contribution of EBV to lymphoma development. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

Downregulation of BLIMP1-alpha by the EBV oncogene, LMP1, disrupts the plasma cell differentiation program and prevents viral replication in B cells: implications for the pathogenesis of EBV-associated B cell lymphomas.

An important pathogenic event in Epstein-Barr virus (EBV)-associated lymphomas is the suppression of virus replication, which would otherwise lead to cell death. Because virus replication in B cells is intimately linked to their differentiation toward plasma cells, we asked whether the physiologic signals that drive normal B-cell differentiation are absent in EBV-transformed cells. We focused on BLIMP1α, a transcription factor that is required for plasma cell differentiation and that is inactivated in diffuse large B-cell lymphomas. We show that BLIMP1α expression is down-regulated after EBV infection of primary germinal center B cells and that the EBV oncogene, latent membrane protein-1 (LMP-1), is alone capable of inducing this down-regulation in these cells. Furthermore, the down-regulation of BLIMP1α by LMP-1 was accompanied by a partial disruption of the BLIMP1α transcriptional program, including the aberrant induction of MYC, the repression of which is required for terminal differentiation. Finally, we show that the ectopic expression of BLIMP1α in EBV-transformed cells can induce the viral lytic cycle. Our results suggest that LMP-1 expression in progenitor germinal center B cells could contribute to the pathogenesis of EBV-associated lymphomas by down-regulating BLIMP1α, in turn preventing plasma cell differentiation and induction of the viral lytic cycle

Hypomethylation and Over-Expression of the Beta Isoform of BLIMP1 is Induced by Epstein-Barr Virus Infection of B Cells; Potential Implications for the Pathogenesis of EBV-Associated Lymphomas

B-lymphocyte-induced maturation protein 1 (BLIMP1) exists as two major isoforms, α and β, which arise from alternate promoters. Inactivation of the full length BLIMP1α isoform is thought to contribute to B cell lymphomagenesis by blocking post-germinal centre (GC) B cell differentiation. In contrast, the shorter β isoform is functionally impaired and over-expressed in several haematological malignancies, including diffuse large B cell lymphomas (DLBCL). We have studied the influence on BLIMP1β expression of the Epstein-Barr virus (EBV), a human herpesvirus that is implicated in the pathogenesis of several GC-derived lymphomas, including a subset of DLBCL and Hodgkin’s lymphoma (HL). We show that BLIMP1β expression is increased following the EBV infection of normal human tonsillar GC B cells. We also show that this change in expression is accompanied by hypomethylation of the BLIMP1β-specific promoter. Furthermore, we confirmed previous reports that the BLIMP1β promoter is hypomethylated in DLBCL cell lines and show for the first time that BLIMP1β is hypomethylated in the Hodgkin/Reed-Sternberg (HRS) cells of HL. Our results provide evidence in support of a role for BLIMP1β in the pathogenesis of EBV-associated B cell lymphomas