Mouse models of non-Hodgkin lymphoma reveal Syk as an important therapeutic target.
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.
Young
Ryan M
RM
Department of Pediatrics, Program in Cell Biology, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Hardy
Ian R
IR
Clarke
Raedun L
RL
Lundy
Nicolai
N
Pine
Polly
P
Turner
Brian C
BC
Potter
Terry A
TA
Refaeli
Yosef
Y
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018390:Gene Targeting; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D000072377:Syk Kinase; D014407:Tumor Cells, Cultured
D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse