Regulation of Mitochondria Function by TRAF3 in B Lymphocytes and B Cell Malignancies
Technical Report,01 Aug 2013,31 Jul 2015
Rutgers, the State University of New Jersey New Brunswick United States
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This project aims to investigate how a new tumor suppressor gene, TRAF3, regulates mitochondria function in B lymphocytes and B cell malignancies. TRAF3 deletions and mutations occur in a variety of B cell malignancies, including B cell chronic lymphocytic leukemia B-CLL, non-Hodgkin lymphoma NHL, such as splenic marginal zone lymphoma and mantle cell lymphoma, multiple myeloma MM, and Waldenstrms macroglobulinemia. We found that specific deletion of TRAF3 from B lymphocytes results in remarkably prolonged survival of mature B cells, which eventually leads to development of splenic marginal zone lymphoma or B1 lymphoma in mice. In this context, understanding how TRAF3 promotes B cell apoptosis is critical for rational design of therapeutic intervention of human B cell neoplasms. In pursuing such underlying mechanisms, we have obtained an unexpected but highly interesting finding. Although it has been widely believed that in the absence of stimulation, TRAF3 protein is evenly distributed in the cytosol, we found that most cellular TRAF3 is localized at mitochondria in resting splenic B cells. This proposal thus aims to test the central hypothesis that TRAF3 directly modulates the physiology of mitochondria to induce apoptosis in B lymphocytes. We will also delineate the profile of proteins assembled in the mitochondrial TRAF3 signaling complex of B cells. Our long-term goal is to gain new insights into the complex mechanisms of B lymphomagenesis, and to identify new therapeutic targets for the treatment of B-CLL, NHL and MM.