Article

Mancao C, Hammerschmidt W.. Epstein-Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood 110: 3715-3721

GSF-National Research Center for Environment and Health Department of Gene Vectors, Munich, Germany.
Blood (Impact Factor: 10.45). 12/2007; 110(10):3715-21. DOI: 10.1182/blood-2007-05-090142
Source: PubMed

ABSTRACT

Many cells latently infected with Epstein-Barr virus (EBV), including certain virus-associated tumors, express latent membrane protein 2A (LMP2A), suggesting an important role for this protein in viral latency and oncogenesis. LMP2A mimics B-cell receptor signaling but can also act as a decoy receptor blocking B-cell receptor (BCR) activation. Studies of peripheral B cells have not resolved this apparent contradiction because LMP2A seems to be dispensable for EBV-induced transformation of these B cells in vitro. We show here that LMP2A is essential for growth transformation of germinal center B cells, which do not express the genuine BCR because of deleterious somatic hypermutations in their immunoglobulin genes. BCR-positive (BCR(+)) and BCR-negative (BCR(-)) B cells are readily transformed with a recombinant EBV encoding a conditional, floxed LMP2A allele, but the survival and continued proliferation of both BCR(+) and BCR(-) B cells is strictly dependent on LMP2A. These findings indicate that LMP2A has potent, distinct antiapoptotic and/or transforming characteristics and point to its role as an indispensable BCR mimic in certain B cells from which human B-cell tumors such as Hodgkin lymphoma originate.

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    • "In epithelial cells, LMP1 induces epithelial-mesenchymal transition (EMT) , and LMP1 expression is associated with metastasis of clinical NPC tumors (Horikawa et al. 2007 ). The other latent membrane protein LMP2A containing 12 transmembrane domains mimics a H.H. Niller et al. constitutively active B cell receptor (Merchant et al. 2000 ; Mancao and Hammerschmidt 2007 ), and it is not as essential for the growthtransformation of primary B cells as LMP1 or EBNA2. Its expression is governed by the LMP2Ap and, in the case of the shorter splice variant in LCs, LMP2B, by the bidirectional promoter LMP1p for both LMP1 and LMP2B. "
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    ABSTRACT: Latent Epstein-Bar virus genomes undergo epigenetic modifications which are dependent on the respective tissue type and cellular phenotype. These define distinct viral epigenotypes corresponding with latent viral gene expression profiles. Viral Latent Membrane Proteins 1 and 2A can induce cellular DNA methyltransferases, thereby influencing the methylation status of the viral and cellular genomes. Therefore, not only the viral genomes carry epigenetic modifications, but also the cellular genomes adopt major epigenetic alterations upon EBV infection. The distinct cellular epigenotypes of EBV-infected cells differ from the epigenotypes of their normal counterparts. In Burkitt lymphoma (BL), nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma (EBVaGC) significant changes in the host cell methylome with a strong tendency towards CpG island hypermethylation are observed. Hypermethylated genes unique for EBVaGC suggest the existence of an EBV-specific "epigenetic signature". Contrary to the primary malignancies carrying latent EBV genomes, lymphoblastoid cells (LCs) established by EBV infection of peripheral B cells in vitro are characterized by a massive genome-wide demethylation and a significant decrease and redistribution of heterochromatic histone marks. Establishing complete epigenomes of the diverse EBV-associated malignancies shall clarify their similarities and differences and further clarify the contribution of EBV to the pathogenesis, especially for the epithelial malignancies, NPC and EBVaGC.
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    • "The detection of LMP2 RNA in BL biopsies has been previously reported (Bell et al., 2006; Niedobitek et al., 1995; Xue et al., 2002), although LMP2 protein expression has not been reported, possibly due to a relatively poor affinity of the available antibodies. Given the known functions of LMP2A, which include signaling through the BCR pathway and modulation of cell death and proliferation in experimental models (Caldwell et al., 1998; Mancao and Hammerschmidt, 2007), its expression in BL would be consistent with the properties of this tumor. "
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    • "LMP2A can block BCR signal transduction and prevent the activation of lytic replication of EBV in LCLs thus maintaining virus latency [9]–[11]. Moreover, LMP2A can act as a BCR mimic, since human B cells, which do not express functional BCR, are rescued from apoptosis when are infected with wild type EBV, but not with EBV lacking LMP2A [12]. In accordance with this, studies in transgenic mice that express LMP2A in B cells have shown that LMP2A expression can promote survival in BCR-negative cells [13], [14]. "
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