EBV Latent Membrane Protein 1 Activates Akt, NFkappaB, and Stat3 in B Cell Lymphomas 
Latent membrane protein 1 (LMP1) is the major oncoprotein of Epstein-Barr virus (EBV). In transgenic mice, LMP1 promotes increased lymphoma development by 12 mo of age. This study reveals that lymphoma develops in B-1a lymphocytes, a population that is associated with transformation in older mice. The lymphoma cells have deregulated cell cycle markers, and inhibitors of Akt, NFkappaB, and Stat3 block the enhanced viability of LMP1 transgenic lymphocytes and lymphoma cells in vitro. Lymphoma cells are independent of IL4/Stat6 signaling for survival and proliferation, but have constitutively activated Stat3 signaling. These same targets are also deregulated in wild-type B-1a lymphomas that arise spontaneously through age predisposition. These results suggest that Akt, NFkappaB, and Stat3 pathways may serve as effective targets in the treatment of EBV-associated B cell lymphomas. 
Author Summary
Epstein-Barr virus (EBV) is linked to the development of multiple cancers, including post-transplant lymphoma, Hodgkin disease, and nasopharyngeal carcinoma. Latent membrane protein 1 (LMP1) is expressed in many EBV-associated cancers and is responsible for most of the altered cellular growth properties that are induced by EBV infection. This study reveals that LMP1 induces lymphomas in B-1a lymphocytes, a cell type that is susceptible to transformation in aged mice. The lymphomas require Akt, NFkappaB, and Stat3 signaling for enhanced growth and survival. The activation of the Stat3, Akt, and NFkappaB signaling pathways likely underlies the ability of LMP1 to promote malignant transformation. 
