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 TRA...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2019-09-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-019-49390-9 |
| _version_ | 1818996626095603712 |
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| author | Amy L. Whillock Nurbek Mambetsariev Wai W. Lin Laura L. Stunz Gail A. Bishop |
| author_facet | Amy L. Whillock Nurbek Mambetsariev Wai W. Lin Laura L. Stunz Gail A. Bishop |
| author_sort | Amy L. Whillock |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T21:32:43Z |
| format | Article |
| id | doaj.art-cabe35fe3e8245a3acd52f3226bbe784 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-20T21:32:43Z |
| publishDate | 2019-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-cabe35fe3e8245a3acd52f3226bbe7842022-12-21T19:26:01ZengNature PortfolioScientific Reports2045-23222019-09-019111210.1038/s41598-019-49390-9TRAF3 regulates the oncogenic proteins Pim2 and c-Myc to restrain survival in normal and malignant B cellsAmy L. Whillock0Nurbek Mambetsariev1Wai W. Lin2Laura L. Stunz3Gail A. Bishop4Department of Microbiology & Immunology, University of IowaDepartment of Microbiology & Immunology, University of IowaDepartment of Microbiology & Immunology, University of IowaDepartment of Microbiology & Immunology, University of IowaDepartment of Microbiology & Immunology, University of IowaAbstract 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.https://doi.org/10.1038/s41598-019-49390-9 |
| spellingShingle | Amy L. Whillock Nurbek Mambetsariev Wai W. Lin Laura L. Stunz Gail A. Bishop TRAF3 regulates the oncogenic proteins Pim2 and c-Myc to restrain survival in normal and malignant B cells Scientific Reports |
| title | TRAF3 regulates the oncogenic proteins Pim2 and c-Myc to restrain survival in normal and malignant B cells |
| title_full | TRAF3 regulates the oncogenic proteins Pim2 and c-Myc to restrain survival in normal and malignant B cells |
| title_fullStr | TRAF3 regulates the oncogenic proteins Pim2 and c-Myc to restrain survival in normal and malignant B cells |
| title_full_unstemmed | TRAF3 regulates the oncogenic proteins Pim2 and c-Myc to restrain survival in normal and malignant B cells |
| title_short | TRAF3 regulates the oncogenic proteins Pim2 and c-Myc to restrain survival in normal and malignant B cells |
| title_sort | traf3 regulates the oncogenic proteins pim2 and c myc to restrain survival in normal and malignant b cells |
| url | https://doi.org/10.1038/s41598-019-49390-9 |
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