Lyn and Syk activate resistance pathways

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.