title: Emu-BCL10 mice exhibit constitutive activation of both canonical and noncanonical NF-kappaB pathways generating marginal zone (MZ) B-cell expansion as a precursor to splenic MZ lymphoma.
abstract: BCL10, required for nuclear factor kappaB (NF-kappaB) activation during antigen-driven lymphocyte responses, is aberrantly expressed in mucosa-associated lymphoid tissue-type marginal zone (MZ) lymphomas because of chromosomal translocations. Emu-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-kappaB signaling pathways is associated with increased expression of NF-kappaB 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.
authors.affiliation: Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Li
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Wang
authors.forename: Liquan
authors.initials: L
authors.lastname: Xue
authors.forename: Dong-Mi
authors.initials: DM
authors.lastname: Shin
authors.forename: Derry
authors.initials: D
authors.lastname: Roopenian
authors.forename: Wu
authors.initials: W
authors.lastname: Xu
authors.forename: Chen-Feng
authors.initials: CF
authors.lastname: Qi
authors.forename: Mark Y
authors.initials: MY
authors.lastname: Sangster
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Orihuela
authors.forename: Elaine
authors.initials: E
authors.lastname: Tuomanen
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Cui
authors.forename: Quangeng
authors.initials: Q
authors.lastname: Zhang
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Morris
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D056724:Immunity, Humoral; D018442:Lymphoma, B-Cell, Marginal Zone / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013160:Splenic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D016328:NF-kappa B; D011994:Recombinant Proteins
references.citation: Blood. 2008 Oct 1;112(7):2927-34
references.pmid: 18628489
references.citation: Immunity. 2003 Nov;19(5):749-58
references.pmid: 14614861
references.citation: Gut. 2006 Jan;55(1):137-8
references.pmid: 16344587
references.citation: J Immunol. 2004 Jul 1;173(1):15-9
references.pmid: 15210753
references.citation: Lab Invest. 2003 Mar;83(3):357-65
references.pmid: 12649336
references.citation: Science. 1999 Jul 2;285(5424):113-6
references.pmid: 10390361
references.citation: Immunity. 2006 Sep;25(3):403-15
references.pmid: 16973390
references.citation: J Immunol. 2002 Oct 15;169(8):4314-21
references.pmid: 12370363
references.citation: Blood. 2005 Aug 1;106(3):1037-41
references.pmid: 15845895
references.citation: Blood. 2003 Mar 15;101(6):2335-9
references.pmid: 12406890
references.citation: EMBO J. 1994 May 1;13(9):2124-30
references.pmid: 8187765
references.citation: Immunity. 2003 Jun;18(6):763-75
references.pmid: 12818158
references.citation: J Exp Med. 2003 Jan 6;197(1):87-99
references.pmid: 12515816
references.citation: Nat Rev Immunol. 2004 May;4(5):348-59
references.pmid: 15122200
references.citation: Am J Pathol. 1999 Mar;154(3):805-12
references.pmid: 10079258
references.citation: J Exp Med. 2000 Oct 16;192(8):1175-82
references.pmid: 11034607
references.citation: Immunity. 2006 Nov;25(5):701-15
references.pmid: 17098202
references.citation: Nat Immunol. 2003 Sep;4(9):857-65
references.pmid: 12910267
references.citation: Nat Rev Immunol. 2006 Nov;6(11):799-812
references.pmid: 17063183
references.citation: J Immunol. 2007 Nov 1;179(9):5947-57
references.pmid: 17947668
references.citation: Blood. 2002 Jul 1;100(1):246-58
references.pmid: 12070034
references.citation: Cancer Res. 2006 May 15;66(10):5270-7
references.pmid: 16707452
references.citation: Hematol Oncol. 2000 Mar;18(1):1-13
references.pmid: 10797525
references.citation: Cancer Res. 2007 Mar 15;67(6):2439-47
references.pmid: 17363561
references.citation: Immunol Rev. 2003 Aug;194:8-18
references.pmid: 12846803
references.citation: Haematologica. 2006 Dec;91(12):1693-6
references.pmid: 17145608
references.citation: Nature. 2004 Jan 8;427(6970):167-71
references.pmid: 14695475
references.citation: Blood. 2005 Sep 15;106(6):2105-12
references.pmid: 15878976
references.citation: Cell. 2001 Jan 12;104(1):33-42
references.pmid: 11163238
references.citation: J Exp Med. 2006 Apr 17;203(4):1081-91
references.pmid: 16606676
references.citation: Blood. 2004 Oct 15;104(8):2247-53
references.pmid: 15251985
references.citation: Mol Cell Biol. 2004 May;24(9):3860-73
references.pmid: 15082780
references.citation: Arthritis Rheum. 2003 Dec;48(12):3475-86
references.pmid: 14673998
references.citation: Genome Res. 2003 Jul;13(7):1719-27
references.pmid: 12840047
references.citation: Blood. 2005 Dec 15;106(13):4210-6
references.pmid: 16123224
references.citation: Eur J Immunol. 2007 Dec;37(12):3339-51
references.pmid: 18034429
references.citation: Curr Opin Immunol. 2002 Apr;14(2):241-9
references.pmid: 11869899
references.citation: Science. 2003 Nov 28;302(5650):1581-4
references.pmid: 14576442
references.citation: Leukemia. 2007 Mar;21(3):389-96
references.pmid: 17230229
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4514-9
references.pmid: 11930006
references.citation: Blood. 2004 Jan 15;103(2):679-88
references.pmid: 14504101
references.citation: Curr Opin Immunol. 2007 Jun;19(3):327-36
references.pmid: 17433868
references.citation: J Immunol. 1999 Jun 15;162(12):7198-207
references.pmid: 10358166
references.citation: Immunity. 2004 Jun;20(6):785-98
references.pmid: 15189742
references.citation: Cancer Res. 2008 Nov 15;68(22):9202-11
references.pmid: 19010892
references.citation: J Clin Exp Hematop. 2007 Nov;47(2):31-42
references.pmid: 18040143
references.citation: J Pathol. 2005 Feb;205(3):293-301
references.pmid: 15682443
references.citation: Immunity. 2001 May;14(5):617-29
references.pmid: 11371363
references.citation: Trends Immunol. 2001 Jul;22(7):356-60
references.pmid: 11429318
references.citation: Nat Immunol. 2007 Sep;8(9):984-91
references.pmid: 17660823