Proposed model of TLR9 signaling in CLL cells. Activation of TLR9 signaling through CpG ODN mediates phosphorylation of Src in both Zap-70–positive and Zap-70–negative subsets of CLL. In Zap-70–positive cells, phosphorylation of Syk in the SH2 domain (tyrosine 352) and in the kinase domain (tyrosine 525/526) fully activates Syk, which mediates the production and secretion of autoreactive IgM. Subsequently, in an autocrine feedback loop, BCR signaling further engages Syk, and the proapoptotic Bim is degraded (left). In ZAP-70–negative CLL, TLR9 signaling mediates the activation of Src and accumulation of Bim. However, the signal is not transduced to Syk (right).