Title: TRAF3 regulates the oncogenic proteins Pim2 and c-Myc to restrain survival in normal and malignant B cells.

Authors: Whillock, Amy L; Mambetsariev, Nurbek; Lin, Wai W; Stunz, Laura L; Bishop, Gail A

Published In Sci Rep, (2019 09 09)

Abstract: TRAF3 is a versatile intracellular adapter protein with multiple context-specific roles. Uniquely in B cells, TRAF3 deficiency enhances survival and increases the risk of transformation, as loss of TRAF3 is observed in several types of B cell cancers. Here, we report a new mechanism for TRAF3 in the restraint of B cell survival. We found that TRAF3 deficiency was associated with induction of the pro-survival kinase Pim2 in mouse primary B cells and human malignant B cell lines. The increase in Pim2 was independent of NF-κB2 activation but was ameliorated with inhibition of STAT3 expression or function. TRAF3 deficiency also led to a Pim2-dependent increase in c-Myc protein levels and was associated with reduced c-Myc ubiquitination. TRAF3-deficient primary B cells were less sensitive to cell death induced by the Pim inhibitors SGI-1776 and TP-3654. Interestingly, human malignant B cell lines with low expression of TRAF3 were more sensitive to Pim inhibition-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. TRAF3 thus suppresses a Pim2-mediated B cell survival axis, which can be a potential target for treatment of B cell malignancies.

PubMed ID: 31501481

MeSH Terms: Animals; B-Lymphocytes/metabolism; Cell Line, Tumor; Cell Survival; Gene Expression Regulation, Neoplastic*; Humans; Mice; Phosphorylation; Protein-Serine-Threonine Kinases/metabolism*; Proto-Oncogene Proteins c-myc/metabolism*; Proto-Oncogene Proteins/metabolism*; STAT3 Transcription Factor/metabolism; TNF Receptor-Associated Factor 3/deficiency; TNF Receptor-Associated Factor 3/metabolism*