Epstein-Barr virus-associated B-cell lymphomas: pathogenesis and clinical outcomes

Abstract

Epstein-Barr virus (EBV) is a ubiquitous human γ-herpesvirus that establishes a life-long asymptomatic infection in immunocompetent hosts. It is also found to be frequently associated with a broad spectrum of B-cell lymphomas predominantly seen in immunodeficient patients. Despite many resemblances, these EBV-linked lymphoproliferative disorders display heterogeneity at the clinical and the molecular level. Moreover, EBV-associated lymphoproliferative diseases differ in their differential expression patterns of the EBV-encoded latent antigens, which are directly related to their interactions with the host. EBV-driven primary B-cell immortalization is linked to the cooperative functions of these latent proteins, which are critical for perturbing many important cell-signaling pathways maintaining B-cell proliferation. Additionally, it is used as a surrogate model to explore the underlying mechanisms involved in the development of B-cell neoplasms. Recent discoveries have revealed that a number of sophisticated mechanisms are exploited by EBV during cancer progression. This finding will be instrumental in the design of novel approaches for therapeutic interventions against EBV-associated B-cell lymphomas. This review limits the discussion to the biology and pathogenesis of EBV-associated B-cell lymphomas and the related clinical implications.

Figure 1. The salient features of EBV latent antigens in B-cell lymphomas

After initial infection of oropharyngeal epithelial cells (a) EBV primarily infects naïve B-cells (b) and subsequently the infected B-cells are growth transformed (latency III), expressing the full repertoire of latent antigens (c). EBNA-1 tethers viral episome to host chromosome and assists viral replication and segregation (d). EBNA-1 blocks the interaction between p53 and HAUSP and induces its degradation (e). EBNA-2 regulates a wide range of both viral (f) and cellular (g) gene transcription via RBP-Jκ. EBNA-LP promotes EBNA-2 mediated gene transcription (h). EBNA-3 proteins (-3A, -3B and -3C) by blocking EBNA-2 association with RBP-Jκ modulate viral gene transcription as well as Notch signaling pathway (i). EBNA-3C forms a ternary complex with p53 and Mdm2, recruits the Mdm2 E3 ligase activity to ease its degradation and blocks p53-dependent apoptosis (j). EBNA-3C binds to and enhances the kinase activity of both Cyclin D1/CDK6 (k) and Cyclin A/CDK2 (l) complexes to phosphorylate pRb. In addition, EBNA-3C recruits SCF^Skp2 E3 ligase activity on hyperphophorylated pRb (m) and p27^KIP1 (n) for degradation, thereby facilitating the transition of G1 to S phase. LMP-1 inhibits p53-mediated apoptosis by transactivating bcl-2 and A20 genes (o). LMP-1 augments NF-κB signaling to transactivate numerous cellular genes via interaction with tumor necrosis factor receptors (TNFR)-associated factors (TRAFs) and TNFR-associated death domain protein (TRADD) (p). LMP-1 also modulates JAK/STAT, ERK MAPK, IRF and Wnt signaling pathways (q). LMP-2A blocks B-cell receptor (BCR) signaling through interaction with cellular tyrosine kinases Lyn and Syk (r). LMP-2B regulates LMP-2A function (s). EBERs block apoptosis, bind to La and L22 cellular proteins and induce IL-10 cytokine and type I IFN (t). The biological function of BARTs is under investigation as to their role in development of B-cell lymphoma (u).