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Blood, 5 November 2009, Vol. 114, No. 19, pp. 4158-4168.
Prepublished online as a Blood First Edition Paper on August 20, 2009; DOI 10.1182/blood-2008-12-192583.
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LYMPHOID NEOPLASIA
Eµ-BCL10 mice exhibit constitutive activation of both canonical and noncanonical NF- B pathways generating marginal zone (MZ) B-cell expansion as a precursor to splenic MZ lymphoma
Zhaoyang Li1,*,
Hongsheng Wang1,*,
Liquan Xue2,*,
Dong-Mi Shin1,
Derry Roopenian3,
Wu Xu4,
Chen-Feng Qi1,
Mark Y. Sangster5,
Carlos J. Orihuela6,
Elaine Tuomanen7,
Jerold E. Rehg2,
Xiaoli Cui2,
Quangeng Zhang8,
Herbert C. Morse, III1, and
Stephan W. Morris2
1 Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD;
2 Departments of Pathology and Oncology, St Jude Children's Research Hospital, Memphis, TN;
3 The Jackson Laboratory, Bar Harbor, ME;
4 Department of Chemistry, University of Louisiana at Lafayette;
5 Department of Microbiology, University of Tennessee at Knoxville;
6 Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio;
7 Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN; and
8 Department of Immunology, Capital Medical University, Beijing, People's Republic of China
BCL10, required for nuclear factor  B (NF-B) activation during antigen-driven lymphocyte responses, is aberrantly expressed in mucosa-associated lymphoid tissue-type marginal zone (MZ) lymphomas because of chromosomal translocations. Eµ-driven human BCL10 transgenic (Tg) mice, which we created and characterize here, had expanded populations of MZ B cells and reduced follicular and B1a cells. Splenic B cells from Tg mice exhibited constitutive activation of both canonical and noncanonical NF-B signaling pathways is associated with increased expression of NF-B target genes. These genes included Tnfsf13b, which encodes the B-cell activating factor (BAFF). In addition, levels of BAFF were significantly increased in sera from Tg mice. MZ B cells of Tg mice exhibited reduced turnover in vivo and enhanced survival in vitro, indicative of lymphoaccumulation rather than lymphoproliferation as the cause of MZ expansion. In vivo antibody responses to both T-independent, and especially T-dependent, antigens were significantly reduced in Tg mice. Mortality was accelerated in Tg animals, and some mice older than 8 months had histologic and molecular findings indicative of clonal splenic MZ lymphoma. These results suggest that, in addition to constitutive activation of BCL10 in MZ B cells, other genetic factors or environmental influences are required for short latency oncogenic transformation.
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