The generation of phosphotyrosine residues by Lyn and Syk results in the activation of multiple pathways. Key mechanisms pertinent to cell survival are briefly summarized here.
Activation of Phospho lipase c gamma2 (Plc gamma 2) following BCR engagement results in cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) and the generation of two second messenger molecules, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG binding activates Pkcβ, thus blocking cell death by upregulating transcription of anti-apoptotic genes via nuclear factor-κB (NF-κB).
Binding of IP3 to Ca2+ channels releases Ca2+ ions stored in the endoplasmic reticulum. Released Ca2+ binds calmodulin (Cam) and the Ca2+/Cam complex activates the phosphatase, calcineurin. Activation of the transcription factor NFAT by calcineurin-mediated dephosphorylation results in transcription of several genes including those of IL-2, IL-4 and gamma-interferon, which block apoptosis of CLL cells.
Pkcβ overexpression correlates with poor prognosis in CLL and PRKCB deletion prevents development of CLL-like disease in Eμ-TCL1 transgenic mice, suggesting a key role in CLL pathogenesis. Enzastaurin, an inhibitor targeting both Pkcβ and Akt, induced apoptosis of CLL cells but not of T cells in vitro. A phase I study of this agent has started.
It gets more complicated still. The thing to remember about cell signaling is that there are many back-up systems and blocking one pathway may mean that back-up is called into play. Multiple drugs are probably going to be necessary. In this respect CML and Gleevec are exceptions to the general rule.