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Blood, 12 March 2009, Vol. 113, No. 11, pp. 2508-2516.
Prepublished online as a Blood First Edition Paper on November 3, 2008; DOI 10.1182/blood-2008-05-158618.
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Submitted May 23, 2008
Accepted October 14, 2008
Mouse models of non-Hodgkins lymphoma reveal Syk as an important therapeutic target
Ryan M. Young, Ian R Hardy, Raedun L Clarke, Nicolai Lundy, Polly Pine, Brian C Turner, Terry A Potter, and Yosef Refaeli*
Department of Pediatrics, Program in Cell Biology, National Jewish Medical and Research Center, Denver, CO, United States
Department of Immunology, University of Colorado Denver Health and Sciences Center, Denver, CO, United States
Rigel Pharmaceuticals, South San Francisco, CA, United States
University of Colorado Cancer Center, Aurora, CO, United States
* Corresponding author; email: refaeliy{at}njc.org.
We have generated mouse models of Non-Hodgkin's 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 non-receptor tyrosine kinase required to transduce BCR-dependent signals. Using a genetic approach, we show 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 pharmacological 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 pharmacological 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.
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