Homeostatic survival of B lymphocytes is carefully regulated, and disruption of this regulation is an important factor in pathogenesis of various autoimmune diseases and B cell malignancies. The latter are the most common hematologic cancers in the US population as well as in Veterans, in whom age/gender status, as well as exposures related to their service, can increase risk of B cell cancers. The signaling adapter protein TRAF3 plays an important, B-cell-specific role in restraining homeostatic survival and B cell activation. B cell TRAF3 deficiency in a mouse model causes abnormally high B cell survival that results in accumulation and infiltration of multiple organs and tissue with B cells, autoantibody production, and predisposition to B cell tumors. In humans, mutations of the TRAF3 gene are now recognized as common in B cell lymphoma and multiple myeloma. The proposed project will address the hypothesis that functional TRAF3 deficiency can also be caused by cellular events leading to TRAF3 membrane sequestration and/or degradation. Thus, TRAF3- regulated B cell survival abnormalities can contribute to an even higher proportion of malignancies than just those with genetic TRAF3 mutations. The proposed project will also build upon new information acquired during the most recent funding period, identifying B cell survival pathways regulated by TRAF3. The goals of the project are to determine how cellular signaling results in functional TRAF3 deficiency in B cells, and to identify TRAF3-regulated targetable B cell survival pathways, in both model systems and samples of human B cell malignancies, via the following Specific Aims: 1) Determine the mechanisms and impact of TRAF3- receptor interactions and TRAF3 deficiency on TRAF3-regulated B cell survival pathways. 2) Identify drugs/compounds effective in selectively blocking the abnormally enhanced viability of TRAF3-deficient B cells. 3) Define the association between TRAF3 status and B cell survival pathways, in human B cell malignancies. The expected outcomes of the proposed project are an accurate and detailed understanding of how B cell survival is regulated by TRAF3-mediated pathways, how key pathways can be targeted to counteract enhanced survival of TRAF3-deficient B cells, and how TRAF3 status is related to phenotype in BCL and MM. This knowledge is expected to provide valuable information to inform the best selection of therapeutic options and strategies to prevent and treat drug resistance and recurrence in human B cell malignancies.