B-cell receptor signaling in CLL and targeted inhibition. The diagram shows the major signaling pathways activated after BCR activation. (A) The signalosome is composed of LYN, SYK, BLNK, BTK, PLC-γ2, and PI3K. Chemical inhibition of LYN, SYK, BTK, and PI3K by dasatinib, fostamatinib disodium (FosD), PCI-32765, or CAL-101, respectively, blocks BCR signaling in CLL cells in vitro. The BCR signal can be further enhanced or inhibited by positive and negative coreceptor signaling to control the duration and intensity of the signal. (B) Principal downstream signaling pathways linking the BCR to biologic responses.