A significant percentage of the population is latently infected with Epstein-Barr virus (EBV). In most individuals, no clinical symptoms are evident. However, in a subset of individuals with compromised immune systems, EBV infection is associated with lymphomas, such as Burkitt's and non-Hodgkin's lymphomas (34, 47). Furthermore, approximately 40% of Hodgkin's lymphoma cases are positive for EBV latent infection, suggesting that there is a causal relationship between EBV infection and the occurrence of Hodgkin's lymphoma (31, 32). Most recently, our laboratory has implicated that an EBVencoded protein, latent membrane protein 2A (LMP2A), alters gene expression in a manner similar to that observed in Hodgkin Reed-Sternberg cells. These data indicate that LMP2A may play a role in the development of Hodgkin's lymphoma (46). In addition, LMP2A expression is readily detected in vivo, suggesting that LMP2A plays a critical role in the EBV life cycle (4,5,14,26). Therefore, understanding the functions of EBV latency proteins may allow for therapeutic interventions to prevent or treat EBV latency and subsequent lymphomas.Studies using human lymphoblastoid cell lines (LCLs) demonstrate that LMP2A induces the constitutive phosphorylation of numerous signal transduction proteins utilized by the B-cell receptor (BCR) (such as Lyn, Syk, and phosphatidylinositol 3-kinase [PI3K]) (19,38,46,49). In these LCLs, LMP2A inhibits the BCR-induced activation of these proteins, suggesting that LMP2A blocks BCR signal transduction in latently infected B cells. However, LCLs are immortalized and actively dividing and express numerous EBV proteins, which is quite different from the EBV latency patterns observed in vivo (3,4,26). Thus, studies of LMP2A function in primary B cells are needed to determine how LMP2A alters normal primary BCR signaling in vivo.In humans, the B cells in which EBV resides are rare (1 in 10 5 to 10 6 B cells) (29, 41, 52), and therefore it is difficult to obtain sufficient numbers of B cells to study how EBV alters their normal function. To address this question, we produced transgenic (Tg) mice that express LMP2A in developing B cells (TgE-Tg) (10, 11). These mice produced immunoglobulin M (IgM)-negative B cells that survive and colonize peripheral organs (11,27). It was proposed that LMP2A acted similarly to a pre-BCR during development since LMP2A decreased the expression of proteins important for rearranging the IgM heavy chain (45) and subsequent heavy-chain rearrangement (11). The survival of these IgM-negative B cells further suggested that LMP2A acted as a BCR mimic, since B cells normally undergo apoptosis from a lack of a tonic BCR-derived survival signal (30, 33). More recently, findings from our laboratory have suggested that LMP2A protects B cells from apoptosis by the RAS/PI3K/AKT pathway (19,46). This model revealed a novel function for LMP2A whereby this latently expressed EBV protein provides a surrogate BCR-like stimulus to promote B-cell development and peripheral B-cell survival. Despite the d...

Despite the identification of Epstein-Barr virus (EBV) in tumors of Burkitt's lymphoma (BL) over 40 years ago, the exact contribution of EBV to BL is undefined. EBV encodes for multiple proteins in latent B cells that affect B cell survival and activation. One such protein, latent membrane protein 2A (LMP2A), protects B cells from numerous pro-apoptotic stimuli. Therefore, we tested whether LMP2A protects B cells from apoptosis induced by aberrant c-MYC expression that precedes and dominates BL. We crossed LMP2A-transgenic mice (LMP2A-Tg), in which all B cells express LMP2A, to a transgenic mouse that expresses a BL translocation of myc (k-MYC-Tg mice). LMP2A promotes proliferation and protects B cells from MYC-induced apoptosis in k-MYC-Tg mice. LMP2A also accelerates the development of lymphoma in LMP2A/k-MYC-Tg mice. Finally, LMP2A increases the expression of Bcl-X L in both pretumor B cells and tumor cells, suggesting a mechanism for LMP2A-mediated B cell survival in the presence of MYC. These results support a hypothesis that EBV LMP2A promotes tumor development by protecting pre-tumor B cells that would normally apoptose after the c-myc translocation.

Epstein-Barr virus (EBV) establishes latent infections in

In cell lines, the Epstein–Barr virus (EBV)-encoded protein latent membrane protein 2A (LMP2A) protects B-cells from apoptosis by blocking B-cell receptor (BCR) signalling. However, EBV-infected B-cells in vivo are extremely different from cell lines. This study used a murine transgenic model in which B-cells express LMP2A and a BCR specific for hen egg lysozyme to determine whether LMP2A protects resting and antigen-activated B-cells from apoptosis. LMP2A allows BCR signal transduction and induces constitutive activation of NF-κB to increase Bcl-2 levels that afford LMP2A-mediated protection from apoptosis in the absence or presence of antigen. In contrast, low levels of NF-κB inhibitor only affected Bcl-2 and Bcl-xL levels and increased apoptosis in LMP2A-negative B-cells after BCR cross-linking. These data suggest that LMP2A uniquely makes resting B-cells sensitive to NF-κB inhibition and apoptosis and suggest that NF-κB may be a novel target to eradicate latently EBV-infected B-cells.

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