TRAF3-mediated regulation of survival and BCR signaling in normal and malignant B cells
Creators: name: Whillock, Amy Louise
Publisher: name: University of Iowa
Year: 2022
Subjects: B cell malignancies
BCR
Pim2
TRAF3
public abstract

description: 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.
description: 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.
description: 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.
description: 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.