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

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.

• Authors: Amy L Whillock, Nurbek Mambetsariev, Wai W Lin, Laura L Stunz, Gail A Bishop
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 12884 (09 09 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31501481 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• MYC protein, human
• PIM2 protein, human
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-myc
• STAT3 Transcription Factor
• TNF Receptor-Associated Factor 3
• Protein Serine-Threonine Kinases

Topics

• Animals
• B-Lymphocytes (metabolism)
• Cell Line, Tumor
• Cell Survival
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Phosphorylation
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• STAT3 Transcription Factor (metabolism)
• TNF Receptor-Associated Factor 3 (deficiency, metabolism)