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.
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.
Li
Zhaoyang
Z
Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
Wang
Hongsheng
H
Xue
Liquan
L
Shin
Dong-Mi
DM
Roopenian
Derry
D
Xu
Wu
W
Qi
Chen-Feng
CF
Sangster
Mark Y
MY
Orihuela
Carlos J
CJ
Tuomanen
Elaine
E
Rehg
Jerold E
JE
Cui
Xiaoli
X
Zhang
Quangeng
Q
Morse
Herbert C
HC
Morris
Stephan W
SW
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
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D016328:NF-kappa B; D011994:Recombinant Proteins
Blood. 2008 Oct 1;112(7):2927-34
18628489
Immunity. 2003 Nov;19(5):749-58
14614861
Gut. 2006 Jan;55(1):137-8
16344587
J Immunol. 2004 Jul 1;173(1):15-9
15210753
Lab Invest. 2003 Mar;83(3):357-65
12649336
Science. 1999 Jul 2;285(5424):113-6
10390361
Immunity. 2006 Sep;25(3):403-15
16973390
J Immunol. 2002 Oct 15;169(8):4314-21
12370363
Blood. 2005 Aug 1;106(3):1037-41
15845895
Blood. 2003 Mar 15;101(6):2335-9
12406890
EMBO J. 1994 May 1;13(9):2124-30
8187765
Immunity. 2003 Jun;18(6):763-75
12818158
J Exp Med. 2003 Jan 6;197(1):87-99
12515816
Nat Rev Immunol. 2004 May;4(5):348-59
15122200
Am J Pathol. 1999 Mar;154(3):805-12
10079258
J Exp Med. 2000 Oct 16;192(8):1175-82
11034607
Immunity. 2006 Nov;25(5):701-15
17098202
Nat Immunol. 2003 Sep;4(9):857-65
12910267
Nat Rev Immunol. 2006 Nov;6(11):799-812
17063183
J Immunol. 2007 Nov 1;179(9):5947-57
17947668
Blood. 2002 Jul 1;100(1):246-58
12070034
Cancer Res. 2006 May 15;66(10):5270-7
16707452
Hematol Oncol. 2000 Mar;18(1):1-13
10797525
Cancer Res. 2007 Mar 15;67(6):2439-47
17363561
Immunol Rev. 2003 Aug;194:8-18
12846803
Haematologica. 2006 Dec;91(12):1693-6
17145608
Nature. 2004 Jan 8;427(6970):167-71
14695475
Blood. 2005 Sep 15;106(6):2105-12
15878976
Cell. 2001 Jan 12;104(1):33-42
11163238
J Exp Med. 2006 Apr 17;203(4):1081-91
16606676
Blood. 2004 Oct 15;104(8):2247-53
15251985
Mol Cell Biol. 2004 May;24(9):3860-73
15082780
Arthritis Rheum. 2003 Dec;48(12):3475-86
14673998
Genome Res. 2003 Jul;13(7):1719-27
12840047
Blood. 2005 Dec 15;106(13):4210-6
16123224
Eur J Immunol. 2007 Dec;37(12):3339-51
18034429
Curr Opin Immunol. 2002 Apr;14(2):241-9
11869899
Science. 2003 Nov 28;302(5650):1581-4
14576442
Leukemia. 2007 Mar;21(3):389-96
17230229
Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4514-9
11930006
Blood. 2004 Jan 15;103(2):679-88
14504101
Curr Opin Immunol. 2007 Jun;19(3):327-36
17433868
J Immunol. 1999 Jun 15;162(12):7198-207
10358166
Immunity. 2004 Jun;20(6):785-98
15189742
Cancer Res. 2008 Nov 15;68(22):9202-11
19010892
J Clin Exp Hematop. 2007 Nov;47(2):31-42
18040143
J Pathol. 2005 Feb;205(3):293-301
15682443
Immunity. 2001 May;14(5):617-29
11371363
Trends Immunol. 2001 Jul;22(7):356-60
11429318
Nat Immunol. 2007 Sep;8(9):984-91
17660823