Epstein - Barr virus is an important cause Hodgkin's Disease, Lymphomas, and Lymphoproliferative Diseases, particularly in people with HIV infection and other immune- compromised states. The EBV oncoprotein Latent Membrane Protein 1 transforms B-cells through 2 essential signaling domains for B cell growth: Transformation effect site 1, which activates non- canonical NFkB and site 2, which activates canonical NFkB. Both NFkB pathways are necessary for infected cell growth and survival. To discover key components of LMP1 affected NFkB pathways, our AIMS are to: (1) Characterize key B-cell proteins required for LMP1 TES2 canonical NFkB activation for their role in TRAF6 and IKK activation, NEMO ubiquitination, and nuclear RelA phosphorylation. Candidates for missing kinases, phosphatases, E3 ligases, and scaffolds have been identified through a genome wide siRNA screen in 293 cells and will be evaluated in B cells. (2) Key B-cell proteins required for LMP1 TES1 non-canonical NFkB activation will be identified. This aim will focus on unique LMP1 effects through TRAFs, will employ LMP1 and TRAF genetic analyses and will identify novel cell proteins critical for LMP1-mediated non-canonical NFkB activation. (3) Identifycombinations of AIM 1 and 2 target proteins knockdowns that create synthetic lethal effects, when both are depleted from EBV-transformed B cells. AIM3 experiments exploit what we learn in AIMS 1 and 2 to identify the Achilles' Heel of EBV-associated lymphomas. NFkB small molecule inhibitors that are not specific for LMP1-mediated NFkB activation will likely be limited by side-effects, including inhibition of critical immune responses. These studies specifically address NCI goals outlined in PA10-290 by determining the mechanism by which EBV affects tumor promotion and progression, by discovering novel targets for rational drug discovery for the treatment of persons afflicted with AIDS-defining malignancies, and by using combinatorial genomic methodologies to further development of therapeutic agents. Our discoveries will elucidate new key targets in NFkB activation and more broadly advance priority target-based tool compound discovery.