Scientific Objective and Rationale of the Proposed Project: B lymphocyte is a type of white blood cell and the only cell type of the human body to produce antibodies against various pathogens. Aberrant B cell survival is one important pathogenic factor that leads to B cell malignancies, which comprise >50% of blood cancers. We and others have recently identified TRAF3 as a critical regulator of mature B cell survival. Interestingly, TRAF3 deletions and mutations occur in a variety of B cell neoplasms, including B cell chronic lymphocytic leukemia (B-CLL), non-Hodgkin lymphoma (NHL), as well as multiple myeloma (MM) and Waldenström's macroglobulinemia (WM). In this context, understanding how TRAF3 inhibits B cell survival is critical for rational design of therapeutic intervention of human B cell malignancies. In pursuing the underlying mechanisms of TRAF3-induced B cell death, we have obtained two unexpected but highly interesting findings: (1) TRAF3 does not modulate the expression, phosphorylation, or cleavage of the Bcl2 family proteins. (2) TRAF3 is primarily localized at mitochondria in resting splenic B cells, but not evenly distributed in the cytosol as widely believed. Mitochondrion is a type of subcellular organelle that is required for energy production as well as the control of cell death and cell cycle. Our new findings indicate that the mechanism of TRAF3-induced B cell death is distinct from that previously envisaged. This proposal thus aims to discover novel mechanisms of TRAF3-induced B cell death. We will vigorously test the central hypothesis that TRAF3 directly modulates the physiology of mitochondria to induce B cell death. We will also delineate the profile of proteins assembled in the mitochondrial TRAF3 signaling complex of B lymphocytes. Our long-term goal is to gain new insights into the complex mechanisms of B cell death and oncogenic B cell survival and to identify new therapeutic targets for the prevention and treatment of B cell malignancies.Principal Investigator's Career Goals: Dr. Ping Xie's (the Principal Investigator) career goal is to establish himself as an outstanding professor in blood cancer research. With the support of this award, Dr. Xie will have the opportunity to complete additional training in hypothesis formulation and collaborations, grant writing, mentoring and supervision of trainees, meeting organization, and multi-task handling, etc. This award will also provide Dr. Xie with research support to identify novel mitochondrial TRAF3-interacting proteins in B lymphocytes, which will undoubtedly open up exciting new research areas for Dr. Xie and form the foundation for her future research grants. Taken together, this DoD award will provide critical support to enable Dr. Xie to acquire superior competence, leadership skills, and additional research expertise to achieve her research and career goals.Ultimate Applicability of the Proposed Research: Our study will directly lead to discovery of novel regulators and mechanisms of B cell survival and death. The novel regulators of B cell survival may represent new genetic risk factors and may serve as biomarkers for early detection and diagnosis of B cell malignancies. Clinical application of diagnostic/prognostic markers discovered by our study will be achievable within 3 years of the publication of our findings. Furthermore, identification of novel regulators and understanding of new mechanisms of B cell survival will be applied to develop new therapeutic strategies and drugs for the prevention and treatment of B cell neoplasms. Thus, our proposed research will provide valuable information to help patients with B cell malignancies, the most common blood cancers. Taken together, our proposed study will contribute to deciphering the molecular basis of B cell malignancies, as well as rapid identification of new biomarkers and therapeutic targets that will benefit patients with B-CLL, NHL, MM, and WM.Likely Contributions of This Study to Advancing the Field in Cancer Research: Our new evidence challenges the current paradigm about TRAF3-induced B cell death, which involves inhibition of the transcription factor NF-kappaB2 and suppression of survival proteins of the Bcl2 family. Our proposed study will provide new insights towards understanding the regulatory mechanisms of mitochondrion physiology, B cell death, and oncogenic B cell survival. Such fundamental understanding will significantly advance the field of blood cancer research.Impact and Relevance to Military Beneficiaries: TRAF3 inactivation frequently occurs in a variety of B cell neoplasms, including B-CLL, NHL, MM, and WM. Notably, military personnel and veterans have increased risk of TRAF3 inactivation, which is induced by the Epstein-Barr virus-encoded oncoprotein LMP1, mutations, infections, and inflammations, due to duty environment, bioterror weapons, physical injury, stress, etc. Our proposed study will identify novel regulators and mechanisms of B cell survival and thus open up new avenues for the prevention and treatment of B cell malignancies, which constitute >50% of blood cancers.
|Effective start/end date||8/1/13 → 7/31/15|
- Congressionally Directed Medical Research Programs (CDMRP)