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.

Public Health Relevance

The proposed project focuses on a protein called TRAF3 that prevents abnormal survival of B cells, the type of white blood cell that produces antibodies. Cancers of B cells are the most common type of blood cell cancer, and are currently approximately 5% of all cancers in the US. The incidence of B cell cancers has been steadily increasing over the past 40 years. Importantly, the specific types of B cell cancers most relevant to the proposed studies are considered `presumptive diseases' of Veterans who were exposed to ionizing radiation or herbicides like Agent Orange during their service, and mutations in TRAF3 are common in these cancers. The proposed work will determine how TRAF3 normally prevents excess B cell survival, how abnormal survival of B cells lacking normal amounts of TRAF3 occurs, and potential ways this can be blocked.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Hematology (HEMA)
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Iowa City VA Medical Center
Iowa City
United States
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Wallis, Alicia M; Bishop, Gail A (2018) TRAF3 regulation of inhibitory signaling pathways in B and T lymphocytes by kinase and phosphatase localization. J Leukoc Biol :
Bangalore-Prakash, Pradeep; Stunz, Laura L; Mambetsariev, Nurbek et al. (2017) The oncogenic membrane protein LMP1 sequesters TRAF3 in B-cell lymphoma cells to produce functional TRAF3 deficiency. Blood Adv 1:2712-2723
Lin, Wai W; Yi, Zuoan; Stunz, Laura L et al. (2015) The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development. Sci Signal 8:ra88
Lin, Wai W; Hostager, Bruce S; Bishop, Gail A (2015) TRAF3, ubiquitination, and B-lymphocyte regulation. Immunol Rev 266:46-55
Yi, Zuoan; Stunz, Laura L; Lin, Wai Wai et al. (2014) TRAF3 regulates homeostasis of CD8+ central memory T cells. PLoS One 9:e102120
Yi, Zuoan; Lin, Wai Wai; Stunz, Laura L et al. (2014) The adaptor TRAF3 restrains the lineage determination of thymic regulatory T cells by modulating signaling via the receptor for IL-2. Nat Immunol 15:866-74
Ontiveros, Evelena P; Halwani, Ahmad; Stunz, Laura L et al. (2014) A new model of LMP1-MYC interaction in B cell lymphoma. Leuk Lymphoma 55:2917-23
Buchta, Claire M; Bishop, Gail A (2014) TRAF5 negatively regulates TLR signaling in B lymphocytes. J Immunol 192:145-50
Yi, Zuoan; Stunz, Laura L; Bishop, Gail A (2014) CD40-mediated maintenance of immune homeostasis in the adipose tissue microenvironment. Diabetes 63:2751-60
Yi, Zuoan; Lin, Wai Wai; Stunz, Laura L et al. (2014) Roles for TNF-receptor associated factor 3 (TRAF3) in lymphocyte functions. Cytokine Growth Factor Rev 25:147-56

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