Model of mechanism underlying differential effect of innate immune activation on ZAP-70–positive vs ZAP-70–negative CLL. In ZAP-70–positive CLL, activation of TLR9 via CpG induces IgM secretion by a ZAP-70– and Syk-dependent pathway. Robust phosphorylation (P) of Syk results in degradation of the proapoptotic Bim, which is amplified by autocrine stimulation of the B-cell receptor by the secreted IgM. The final effect is CpG-induced CLL cell proliferation and survival. Activation of TLR9 in the absence of ZAP-70 results in cell death. See Figure 7 in the article by Wagner et al that begins on page 436.