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


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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    • "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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    ABSTRACT: We have validated a flexible, high-throughput and relatively inexpensive RT-QPCR array platform for absolute quantification of Epstein–Barr virus transcripts in different latent and lytic infection states. Several novel observations are reported. First, during infection of normal B cells, Wp-initiated latent gene transcripts remain far more abundant following activation of the Cp promoter than was hitherto suspected. Second, EBNA1 transcript levels are remarkably low in all forms of latency, typically ranging from 1 to 10 transcripts per cell. EBNA3A, -3B and -3C transcripts are likewise very low in Latency III, typically at levels similar to or less than EBNA1 transcripts. Thirdly, a subset of lytic gene transcripts is detectable in Burkitt lymphoma lines at low levels, including: BILF1, which has oncogenic properties, and the poorly characterized LF1, LF2 and LF3 genes. Analysis of seven African BL biopsies confirmed this transcription profile but additionally revealed significant expression of LMP2 transcripts.
    Virology 11/2014; 474. DOI:10.1016/j.virol.2014.10.030 · 3.32 Impact Factor
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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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    ABSTRACT: Epstein-Barr virus (EBV) is a human herpesvirus, which is causally associated with the development of several B lymphocytic malignancies that include Burkitt's lymphomas, Hodgkin's disease, AIDS and posttransplant associated lymphomas. The transforming activity of EBV is orchestrated by several latent viral proteins that mimic and modulate cellular growth promoting and antiapoptotic signaling pathways, which involve among others the activity of protein kinases. In an effort to identify small molecule inhibitors of the growth of EBV-transformed B lymphocytes a library of 254 kinase inhibitors was screened. This effort identified two tyrosine kinase inhibitors and two MEK inhibitors that compromised preferentially the viability of EBV-infected human B lymphocytes. Our findings highlight the possible dependence of EBV-infected B lymphocytes on specific kinase-regulated pathways underlining the potential for the development of small molecule-based therapeutics that could target selectively EBV-associated human B lymphocyte malignancies.
    PLoS ONE 04/2014; 9(4):e95688. DOI:10.1371/journal.pone.0095688 · 3.23 Impact Factor
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    • "Meanwhile, latent membrane protein (LMP)-2A, a mimic of functional BCRs, is expressed by EBV potentially to inhibit negative selection. LMP-2A constitutively activates PI3K,96,97 thus providing the cell with the “tonic” BCR-like survival signals that are evident following TCF3 and ID3 mutation in BL. Interestingly, LMP-2A is often detected in tumor biopsies of EBV-related malignancies, although LMP-2A is down-regulated during later stages of viral latency and can, therefore, play no further role in promoting cell survival. "
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    ABSTRACT: Burkitt's lymphoma (BL) is an aggressive disorder associated with extremely high rates of cell proliferation tempered by high levels of apoptosis. Despite the high levels of cell death, the net effect is one of rapid tumor growth. The tumor arises within the germinal centers of secondary lymphoid tissues and is identifiable by translocation of the c-MYC gene into the immunoglobulin gene loci, resulting in deregulation of the proto-oncogene. Many of the major players involved in determining the development of BL have been characterized in human BL cell lines or in mouse models of MYC-driven lymphomagenesis. Both systems have been useful so far in characterizing the role of tumor suppressor genes (for example, p53), prosurvival signaling pathways, and members of the B-cell lymphoma-2 family of apoptosis regulators in determining the fate of c-MYC overexpressing B-cells, and ultimately in regulating lymphoma development. Signaling through phosphoinositide (PI)3-kinase stands out as being critical for BL cell survival. Recurrent mutations in ID3 or TCF3 (E2A) that promote signaling through PI3-kinase have recently been identified in human BL samples, and new therapeutic strategies based on coordinately targeting both the prosurvival factor, B-cell lymphoma-XL, and the PI3-kinase/AKT/mammalian target of rapamycin (mTOR) signaling pathway to synergistically induced BL apoptosis have been proposed. Now, engineering both constitutive c-MYC expression and PI3-kinase activity, specifically in murine B-cells undergoing the germinal center reaction, has revealed that there is synergistic cooperation between c-MYC and PI3-kinase during BL development. The resulting tumors phenocopy the human malignancy, and acquire tertiary mutations also present in human tumors. This model may, therefore, prove useful in further studies to identify functionally relevant mutational events necessary for BL pathogenesis. This review discusses these cooperating interactions, the possible influence of BL tumor-associated viruses, and highlights potential new opportunities for therapeutic intervention.
    Cancer Management and Research 01/2014; 6(1):27-38. DOI:10.2147/CMAR.S37745
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