Epstein–Barr virus LMP2A accelerates MYC-induced lymphomagenesis

Abstract

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 LMP2A bypasses p53 inactivation in a MYC model of lymphomagenesis

“…The LMP2A transgenic mice were crossed with a MYC transgenic line in which the human MYC gene is expressed from the Ig locus (25). Consistent with published results (25,26), wild-type, Tg6 LMP2A, and -MYC spleens were similar in size and weight. In contrast, LMP2A/ -MYC mice had greatly enlarged spleens, 0.55 Ϯ 0.17 g for 6-week-old LMP2A/ -MYC compared with 0.17 Ϯ 0.07 g for 6-week-old -MYC.…”

“…Accelerated tumor onset was observed in LMP2A/ -MYC double transgenics, as well as significantly enlarged spleen size in pretumor mice (26). Here, we report similar observations using a second, phenotypically different LMP2A transgenic line (27).…”

“…2E) generating the increase in spleen size seen in the LMP2A/ -MYC mice compared with -MYC mice. Increased expression of Bcl-X L has been observed in LMP2A/ -MYC tumors (26), and Bcl-X L transgenic mice also demonstrate accelerated tumor onset in an E -MYC model (35). However, we cannot exclude the possibility that a mechanism completely separate from Bcl-X L induction is responsible for the ability of LMP2A to accelerate tumorigenesis and bypass p53 inactivation in the LMP2A/ -MYC model.…”

Using Epstein-Barr Viral Load Assays To Diagnose, Monitor, and Prevent Posttransplant Lymphoproliferative Disorder

“…Some mucosal B lymphocytes additionally express EBNA1 (type 1 latency), which maintains the EBV genome and ensures its propagation to dividing cells (209), and LMP1 and LMP2 (type II latency), which mimic B cell receptor stimulation with JAK/STAT signaling to promote cell proliferation, inhibit apoptosis, and generate long-lived memory B cells (22,200). In PTLD, neoplastic cells often express an even wider range of viral factors, including those listed above plus EBNA-2, -3A, -3B, -3C, and -LP (type III latency), which are associated with NF-B activation, MYC upregulation, major histocompatibility complex (MHC) class 1 repression, and rapid cell proliferation (9,40,54,120,132,175).…”

Epstein-Barr Virus Latent Membrane Protein 2A Promotes Invasion of Nasopharyngeal Carcinoma Cells through ERK/Fra-1-Mediated Induction of Matrix Metalloproteinase 9

“…For example, LMP2A drives constitutive activation of PI-3K/Akt to promote survival of B lymphocytes in the absence of B-cell receptor or to inhibit transforming growth factor ␤1-induced apoptosis (20,48). LMP2A also induces a Hodgkin lymphoma-like gene transcription profile in B cells and accelerates myc-induced lymphomagenesis (8,47). For gastric carcinoma cells, LMP2A promotes their survival through upregulation of survivin and inhibits expression of a tumor suppressor gene, PTEN, through induction of promoter hypermethylation (23,24).…”