B-cell receptor signaling in CLL. (A) The BCR is composed of membrane immunoglobulin bound to CD79a/CD79b. Antigen binding induces CD79a/CD79b ITAM recruitment of Syk and Lyn initiating the signaling cascade. (B) Signalosome complex. Phosphorylation of CD79a/CD79b recruits a number of kinases and adaptor proteins, which form the initial signaling complex of the BCR. (C) Intermediate activation. Signalosome activation recruits a number of additional kinases leading to activation down 3 main pathways: Btk, PLC-γ2, and PI3K. Btk is phosphorylated by itself; Syk, and Lyn, which lead to phosphorylation of PLC-γ2, activation of NFκB; and recruitment of PIP5K. PLC-γ2 is phosphorylated by Btk and Syk and leads to production of DAG and IP3. PI3K activation leads to phosphorylation of PIP2 to PIP3.