NF-κB2 mutation targets TRAF1 to induce lymphomagenesis

被引:40
作者
Zhang, Baochun
Wang, Zhe
Li, Tai
Tsitsikov, Erdyni N.
Ding, Han-Fei
机构
[1] Univ Toledo, Dept Biochem & Canc Biol, Toledo, OH 43614 USA
[2] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA
关键词
D O I
10.1182/blood-2006-11-058446
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The NF-kappa B2 gene is recurrently mutated in human lymphoid malignancies. However, a causal relationship between NF-kappa B2 mutation and lymphomagenesis has not been established. It is also unclear how the mutation may lead to lymphold malignancies. We report the generation of transgenic mice with targeted expression of p80HT, a lymphoma-associated NF-kappa B2 mutant, in lymphocytes. The transgenic mice display a marked expansion of peripheral B cell populations and develop predominantly small B cell lymphomas. p80HT expression has no apparent effect on the proliferation of B cells, but renders them specifically resistant to apoptosis induced by cytokine deprivation and mitogenic stimulation. Lymphocytes and lymphoma cells from p80HT mice express high levels of TRAF1, an antiapoptotic protein also implicated in lymphoid malignancies. p80HT binds the TRAF1 promoter in vivo and activates TRAF1 transcription. Moreover, TRAF1 knockdown abrogates the antiapoptotic activity of p80HT and TRAF1 deficiency reestablishes B cell homeostasis in p80HT mice. These findings demonstrate NF-kappa B2 mutation as an oncogenic event in vivo and suggest a molecular pathway for TRAF1 activation in the pathogenesis of lymphomas.
引用
收藏
页码:743 / 751
页数:9
相关论文
共 49 条
[1]   THE C-MYC ONCOGENE DRIVEN BY IMMUNOGLOBULIN ENHANCERS INDUCES LYMPHOID MALIGNANCY IN TRANSGENIC MICE [J].
ADAMS, JM ;
HARRIS, AW ;
PINKERT, CA ;
CORCORAN, LM ;
ALEXANDER, WS ;
CORY, S ;
PALMITER, RD ;
BRINSTER, RL .
NATURE, 1985, 318 (6046) :533-538
[2]   Tumor necrosis factor receptor-associated factors (TRAFs) - a family of adaptor proteins that regulates life and death [J].
Arch, RH ;
Gedrich, RW ;
Thompson, CB .
GENES & DEVELOPMENT, 1998, 12 (18) :2821-2830
[3]   Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression [J].
Basseres, D. S. ;
Baldwin, A. S. .
ONCOGENE, 2006, 25 (51) :6817-6830
[4]   ANTIIMMUNOGLOBULINS INDUCE DEATH BY APOPTOSIS IN WEHI-231 B-LYMPHOMA CELLS [J].
BENHAMOU, LE ;
CAZENAVE, PA ;
SARTHOU, P .
EUROPEAN JOURNAL OF IMMUNOLOGY, 1990, 20 (06) :1405-1407
[5]   Tumor necrosis factor receptor-associated factors (TRAFs) [J].
Bradley, JR ;
Pober, JS .
ONCOGENE, 2001, 20 (44) :6482-6491
[6]   Nuclear factor (NF)-κB2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses [J].
Caamaño, JH ;
Rizzo, CA ;
Durham, SK ;
Barton, DS ;
Raventós-Suárez, C ;
Snapper, CM ;
Bravo, R .
JOURNAL OF EXPERIMENTAL MEDICINE, 1998, 187 (02) :185-196
[7]  
CHANG CC, 1995, MOL CELL BIOL, V15, P5180
[8]   The Rel/NF-κB family directly activates expression of the apoptosis inhibitor Bcl-xL [J].
Chen, CL ;
Edelstein, LC ;
Gélinas, C .
MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (08) :2687-2695
[9]   Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappa B control [J].
Chu, ZL ;
McKinsey, TA ;
Liu, L ;
Gentry, JJ ;
Malim, MH ;
Ballard, DW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (19) :10057-10062
[10]   Constitutive expression of lymphoma-associated NFKB-2/Lyt-10 proteins is tumorigenic in murine fibroblasts [J].
Ciana, P ;
Neri, A ;
Cappellini, C ;
Cavallo, F ;
Pomati, M ;
Chang, CC ;
Maiolo, AT ;
Lombardi, L .
ONCOGENE, 1997, 14 (15) :1805-1810