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

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

doi:10.1038/s41598-019-49390-9

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

Journal article

Open access

Peer reviewed

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

Amy L Whillock, Nurbek Mambetsariev, Wai W Lin, Laura L Stunz and Gail A Bishop

Scientific reports, Vol.9(1), pp.12884-12

09/09/2019

DOI: 10.1038/s41598-019-49390-9

PMCID: PMC6733949

PMID: 31501481

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https://doi.org/10.1038/s41598-019-49390-9View

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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.

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

TNF Receptor-Associated Factor 3 - metabolism

Details

Title: Subtitle: TRAF3 regulates the oncogenic proteins Pim2 and c-Myc to restrain survival in normal and malignant B cells
Creators: Amy L Whillock - University of Iowa
Nurbek Mambetsariev - University of Iowa
Wai W Lin - University of Iowa
Laura L Stunz - University of Iowa
Gail A Bishop - University of Iowa
Resource Type: Journal article
Publication Details: Scientific reports, Vol.9(1), pp.12884-12
DOI: 10.1038/s41598-019-49390-9
PMID: 31501481
PMCID: PMC6733949
NLM abbreviation: Sci Rep
ISSN: 2045-2322
eISSN: 2045-2322
Grant note: P30 ES005605 / NIEHS NIH HHS T32 AI007485 / NIAID NIH HHS T32 GM007337 / NIGMS NIH HHS I01 BX001702 / BLRD VA P30 CA086862 / NCI NIH HHS T32 AI007533 / NIAID NIH HHS P50 CA097274 / NCI NIH HHS
Language: English
Date published: 09/09/2019
Academic Unit: Microbiology and Immunology; President; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984297437402771

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