Inhibition of antigen-dependent B-cell receptor (BCR) signaling is considered a 
promising therapeutic approach in chronic lymphocytic leukemia (CLL), but 
experimental in vivo evidence to support this view is still lacking. We have now 
investigated whether inhibition of BCR signaling with the selective Syk 
inhibitor fostamatinib disodium (R788) will affect the growth of the leukemias 
that develop in the Eμ-TCL1 transgenic mouse model of CLL. Similarly to human 
CLL, these leukemias express stereotyped BCRs that react with autoantigens 
exposed on the surface of senescent or apoptotic cells, suggesting that they are 
antigen driven. We show that R788 effectively inhibits BCR signaling in vivo, 
resulting in reduced proliferation and survival of the malignant B cells and 
significantly prolonged survival of the treated animals. The growth-inhibitory 
effect of R788 occurs despite the relatively modest cytotoxic effect in vitro 
and is independent of basal Syk activity, suggesting that R788 functions 
primarily by inhibiting antigen-dependent BCR signals. Importantly, the effect 
of R788 was found to be selective for the malignant clones, as no disturbance in 
the production of normal B lymphocytes was observed. Collectively, these data 
provide further rationale for clinical trials with R788 in CLL and establish the 
BCR-signaling pathway as an important therapeutic target in this disease.