Eμ-BCL10 mice exhibit constitutive activation of both canonical and noncanonical NF-κB pathways generating marginal zone (MZ) B-cell expansion as a precursor to splenic MZ lymphoma

Zhaoyang Li, Hongsheng Wang, Liquan Xue, Dong Mi Shin, Derry Roopenian, Wu Xu, Chen Feng Qi, Mark Y. Sangster, Carlos J. Orihuela, Elaine Tuomanen, Jerold E. Rehg, Xiaoli Cui, Quangeng Zhang, Herbert C. Morse, Stephan W. Morris

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37 Scopus citations

Abstract

BCL10, required for nuclear factor κB (NF-κB) 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-κB signaling pathways is associated with increased expression of NF-κB 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.

Original languageEnglish (US)
Pages (from-to)4158-4168
Number of pages11
JournalBlood
Volume114
Issue number19
DOIs
StatePublished - Nov 5 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Li, Z., Wang, H., Xue, L., Shin, D. M., Roopenian, D., Xu, W., Qi, C. F., Sangster, M. Y., Orihuela, C. J., Tuomanen, E., Rehg, J. E., Cui, X., Zhang, Q., Morse, H. C., & Morris, S. W. (2009). Eμ-BCL10 mice exhibit constitutive activation of both canonical and noncanonical NF-κB pathways generating marginal zone (MZ) B-cell expansion as a precursor to splenic MZ lymphoma. Blood, 114(19), 4158-4168. https://doi.org/10.1182/blood-2008-12-192583