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Specific deletion of TRAF3 in B lymphocytes leads to B-lymphoma development in mice

Leukemia volume 26, pages 1122–1127 (2012)Cite this article

TRAF3, a cytoplasmic adaptor protein, was recently identified as a candidate tumor suppressor in a range of human B-cell lineage neoplasms. Homozygous deletions and inactivating mutations of the Traf3 gene were detected in non-Hodgkin lymphoma, including splenic marginal zone lymphoma (MZL), B-cell chronic lymphocytic leukemia, mantle cell lymphoma, as well as multiple myeloma and Waldenström's macroglobulinemia.1, 2, 3, 4 However, whether TRAF3 deletions or mutations have a causative role in B lymphomagenesis awaits further in vivo study using TRAF3-knockout mice.

We have recently generated a conditional loss-of-function allele of the Traf3 gene that allows specific deletion of TRAF3 in B lymphocytes in mice (B-TRAF3−/− mice).5 These mice exhibit greatly expanded B-cell populations in secondary lymphoid organs, due to remarkably prolonged, BAFF-independent survival of mature B cells, a finding subsequently confirmed by Gardam et al.6 TRAF3 and TRAF2 assemble to form a regulatory complex with cIAP1/2 and NIK to inhibit the NF-κB2-signaling pathway.7, 8 These observations define a central role of the TRAF3–NIK–NF-κB2 axis in regulating B-cell survival. Prolonged survival of B cells is a known predisposing factor to the development of autoimmunity and B lymphoma.9, 10 Indeed, aging B-TRAF3−/− mice developed high levels of serum autoantibodies to double-stranded DNA as well as immune-complex glomerulonephritis.5 Autoimmunity itself is recognized as a risk factor of B lymphoma in patients with systemic lupus erythematosus or Sjogren's syndrome.11 Hence, B-TRAF3−/− mice may be predisposed to B-cell malignancies. Here we report that B-TRAF3−/− mice spontaneously developed clonal splenic MZL or B1a lymphomas by the age of 18 months.

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Acknowledgements

We are grateful to Dr Janet Hartley for expert advice on mouse B-lymphoma dissection, and Dr Hongsheng Wang for expert advice on IgH VDJ cloning as well as for the critical review of the manuscript. We also thank Jessica Kim, Anano Zangaladze and Will Meng for providing technical assistance to this study. This study was supported by a seed grant from the New Jersey Commission on Cancer Research (10-1066-CCR-EO, P Xie), a Busch Biomedical Grant (P Xie), and the Arthur Herrmann Endowed Cancer Research Fund (P Xie), and in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (H Morse III). The FACS analyses described in this paper were supported by the Flow Cytometry Core Facility of The Cancer Institute of New Jersey (P30CA072720).

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Authors and Affiliations

  1. Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA

    C R Moore, Y Liu, L R Covey & P Xie

  2. Department of Genetics, Rutgers University, Piscataway, NJ, USA

    C Shao

  3. Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA

    H C Morse III

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  1. C R Moore
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Correspondence to P Xie.

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Moore, C., Liu, Y., Shao, C. et al. Specific deletion of TRAF3 in B lymphocytes leads to B-lymphoma development in mice. Leukemia 26, 1122–1127 (2012). https://doi.org/10.1038/leu.2011.309

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