Mouse models of non-Hodgkin lymphoma reveal Syk as an important therapeutic target

被引:101
作者
Young, Ryan M. [1 ,2 ]
Hardy, Ian R. [2 ]
Clarke, Raedun L. [2 ]
Lundy, Nicolai [1 ]
Pine, Polly [3 ]
Turner, Brian C. [1 ]
Potter, Terry A. [2 ]
Refaeli, Yosef [1 ,2 ,4 ]
机构
[1] Natl Jewish Med & Res Ctr, Dept Pediat, Cell Biol Program, Denver, CO 80206 USA
[2] Univ Colorado, Denver Hlth & Sci Ctr, Dept Immunol, Aurora, CO USA
[3] Rigel Pharmaceut, San Francisco, CA USA
[4] Univ Colorado, Ctr Canc, Aurora, CO USA
关键词
B-CELL DEVELOPMENT; CHRONIC LYMPHOCYTIC-LEUKEMIA; TYROSINE KINASE SYK; ANTIGEN-RECEPTOR; RNA INTERFERENCE; MALT-LYMPHOMA; ACTIVATION; IMMUNOGLOBULIN; MECHANISMS; APOPTOSIS;
D O I
10.1182/blood-2008-05-158618
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We have generated mouse models of non-Hodgkin lymphoma (NHL) that rely on the cooperation between MYC overexpression and B-cell antigen receptor (BCR) signaling for the initiation and maintenance of B-cell lymphomas. Using these mouse models of NHL, we have focused on the identification of BCR-derived signal effectors that are important for the maintenance of NHL tumors. In the present study, we concentrate on Spleen tyrosine kinase (Syk), a nonreceptor tyrosine kinase required to transduce BCR-dependent signals. Using a genetic approach, we showed that Syk expression is required for the survival of murine NHL-like tumors in vitro and that tumor cells deficient in Syk fail to expand in vivo. In addition, a pharmacologic inhibitor of Syk was able to induce apoptosis of transformed B cells in vitro and led to tumor regression in vivo. Finally, we show that genetic or pharmacologic inhibition of Syk activity in human NHL cell lines are generally consistent with results found in the mouse models, suggesting that targeting Syk may be a viable therapeutic strategy. (Blood. 2009;113:2508-2516)
引用
收藏
页码:2508 / 2516
页数:9
相关论文
共 38 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]   R406, an orally available spleen tyrosine kinase inhibitor blocks Fc receptor signaling and reduces immune complex-mediated inflammation [J].
Braselmann, Sylvia ;
Taylor, Vanessa ;
Zhao, Haoran ;
Wang, Su ;
Sylvain, Catherine ;
Baluom, Muhammad ;
Qu, Kunbin ;
Herlaar, Ellen ;
Lau, Angela ;
Young, Chi ;
Wong, Brian R. ;
Lovell, Scott ;
Sun, Thomas ;
Park, Gary ;
Argade, Ankush ;
Jurcevic, Stipo ;
Pine, Polly ;
Singh, Rajinder ;
Grossbard, Elliott B. ;
Payan, Donald G. ;
Masuda, Esteban S. .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2006, 319 (03) :998-1008
[3]  
Casella G, 2001, ANTICANCER RES, V21, P1499
[4]   SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma [J].
Chen, Linfeng ;
Monti, Stefano ;
Juszczynski, Przemyslaw ;
Daley, John ;
Chen, Wen ;
Witzig, Thomas E. ;
Habermann, Thomas M. ;
Kutok, Jeffery L. ;
Shipp, Margaret A. .
BLOOD, 2008, 111 (04) :2230-2237
[5]   SYK TYROSINE KINASE REQUIRED FOR MOUSE VIABILITY AND B-CELL DEVELOPMENT [J].
CHENG, AM ;
ROWLEY, B ;
PAO, W ;
HAYDAY, A ;
BOLEN, JB ;
PAWSON, T .
NATURE, 1995, 378 (6554) :303-306
[6]   B cell antigen receptor signaling 101 [J].
Dal Porto, JM ;
Gauld, SB ;
Merrell, KT ;
Mills, D ;
Pugh-Bernard, AE ;
Cambier, J .
MOLECULAR IMMUNOLOGY, 2004, 41 (6-7) :599-613
[7]   LEUKEMIA AND AUTO-IMMUNIZATION - SOME POSSIBLE RELATIONSHIPS [J].
DAMESHEK, W ;
SCHWARTZ, RS .
BLOOD, 1959, 14 (10) :1151-1158
[8]   NUCLEAR-CHANGES IN APOPTOSIS [J].
EARNSHAW, WC .
CURRENT OPINION IN CELL BIOLOGY, 1995, 7 (03) :337-343
[9]   Signaling pathways activated by antigen-receptor engagement in chronic lymphocytic leukemia B-cells [J].
Efremov, Dimitar G. ;
Gobessi, Stefania ;
Longo, Pablo G. .
AUTOIMMUNITY REVIEWS, 2007, 7 (02) :102-108
[10]   Surface μ heavy chain signals down-regulation of the V(D)J-recombinase machinery in the absence of surrogate light chain components [J].
Galler, GR ;
Mundt, C ;
Parker, M ;
Pelanda, R ;
Mårtensson, IL ;
Winkler, TH .
JOURNAL OF EXPERIMENTAL MEDICINE, 2004, 199 (11) :1523-1532