The diagram illustrates PLCG2^R665W-mediated ibrutinib resistance. In treatment naïve CLL, proximal BCR signaling triggers downstream BTK activation. PLCγ2 is consequently activated in a BTK-dependent manner. Targeting BTK by ibrutinib can abrogate PLCγ2-initiated downstream survival signal (left panel); in contrast, mutant PLCγ2 (R665W) can be activated via SYK or LYN, bypassing BTK dependency in the resistant CLL, thereby propagating downstream survival signals despite ibrutinib treatment (right panel). PKC, protein kinase C.