Dissertation
TRAF3-mediated regulation of survival and BCR signaling in normal and malignant B cells
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2022
DOI: 10.25820/etd.006455
Abstract
Tumor necrosis factor receptor-associated factor 3 (TRAF3) plays a vital role in regulating signaling in a cell-type and pathway-specific manner. TRAF3 inhibits signaling by several receptors that are important for B cell functions, including the B cell activating factor (BAFF) receptor, CD40, toll-like receptors, and the IL-6 receptor. Deletions or inactivating mutations of the TRAF3 gene are frequently found in human B cell malignancies, particularly multiple myeloma and lymphoma. B cell-specific TRAF3-deficient (B-Traf3-/-) mice have enlarged secondary lymphoid organs due to the accumulation of B cells and increased homeostatic B cell survival. B-Traf3-/- mice develop spontaneous germinal centers, autoantibody production, and autoimmune manifestations. A majority of aged B-Traf3-/- mice develop B cell lymphomas, showing that TRAF3 acts as a tumor suppressor in B cells. The goal of this project is to better define the mechanisms of TRAF3-mediated restraint of B cell survival in order to better target B cell malignancies.
In the first part of this thesis, TRAF3 deficiency was associated with induction of the pro-survival kinase Pim2 in mouse primary B cells and human malignant B cell lines (Chapter 3). The increase in Pim2 was independent of enhanced NF-κB2 activation but dependent on STAT3 expression and function. TRAF3 deficiency also led to reduced c-Myc polyubiquitination and a Pim2-dependent increase in c-Myc protein. TRAF3-deficient primary B cells were less sensitive to cell death induced by the Pim inhibitors SGI-1776 and TP-3654. In contrast, human malignant B cell lines with low expression of TRAF3 were more sensitive to Pim inhibitor-induced cell death. Combination treatment of TRAF3-deficient B cells and B cell tumor lines with c-Myc inhibitors enhanced their sensitivity to Pim inhibition, suggesting a possible therapeutic strategy to avoid the complications of high-dose Pim inhibitors. TRAF3 thus suppresses a Pim2-mediated B cell survival axis, which can be a potential target for the treatment of B cell malignancies.
The second part of this thesis demonstrates that TRAF3 is an inhibitor of B cell receptor (BCR) signaling. The BCR is crucial for antigen recognition, survival, proliferation, and antibody production, and defects in BCR signaling can promote abnormal survival of malignant B cells. TRAF3 associated with both CD79B of the BCR complex and the BCR-activated kinases Syk and Btk. BCR-induced phosphorylation of Syk and additional downstream kinases was increased in TRAF3-/- B cells, with similar regulation observed in follicular and marginal zone B cell subsets. BCR stimulation of TRAF3-/- B cells resulted in increased surface expression of MHC-II, CD80, and CD86. Interestingly, the increased survival of TRAF3-/- primary B cells was resistant to inhibition of Btk, while TRAF3-deficient malignant B cell lines showed enhanced sensitivity to Btk inhibitor-induced cell death. This shows that TRAF3 works to restrain normal and malignant BCR signaling and survival.
These findings highlight the role of TRAF3 in normal B cell biology and abnormal survival of malignant B cells. This information has important implications for more precise and effective therapeutic choices for the treatment of TRAF3-deficient B cell malignancies.
Details
- Title: Subtitle
- TRAF3-mediated regulation of survival and BCR signaling in normal and malignant B cells
- Creators
- Amy Louise Whillock
- Contributors
- Gail A Bishop (Advisor)Jon C Houtman (Committee Member)John D Colgan (Committee Member)Scott M Lieberman (Committee Member)Miles A Pufall (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Immunology
- Date degree season
- Spring 2022
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.006455
- Number of pages
- xviii, 156 pages
- Copyright
- Copyright 2021 Amy Louise Whillock
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 128-156).
- Public Abstract (ETD)
B cells are the cells responsible for making antibodies to fight infections. However, most blood cancers come from B cells that acquired mutations in genes that normally restrain their survival. The pre-cancerous cells then have time to acquire other mutations that can allow them to divide more quickly and invade other parts of the body. Tumor necrosis factor receptor associated factor 3 (TRAF3) is a protein that is commonly lost or inactivated in blood cancers. Mice without TRAF3 in their B cells has accumulate B cells that can develop into cancer. Instead of dividing faster, B cells without TRAF3 survive for much longer than normal B cells. The overall goal of this project is to understand what TRAF3 is doing in B cells to limit their survival and prevent cancer so that we can develop targeted therapies for B cell cancers.
In the first part of this project, we find that TRAF3 restrains Pim2 and c-Myc, two proteins that promote the development of cancer. We also find that Pim2 and c-Myc inhibitors can be used to kill TRAF3-deficient B cells. The second part of this project focuses on how TRAF3 inhibits signals sent via the B cell receptor (BCR), which is the receptor responsible for specificity of the B cell immune response. Many B cell cancers rely upon signals from the BCR in order to survive so the BCR pathway is a good potential target for therapies. This work has important implications for understanding the development of B cell cancers and choosing therapies to target TRAF3-deficient B cell cancers.
- Academic Unit
- Immunology Graduate Program
- Record Identifier
- 9984271454302771
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