I am grateful to Wayne for drawing my attention to a paper I missed from last June. It is a signaling paper which fills in some of the gaps in the complicated arrangement that CLL cells have to send messages from the BCR. It has already been established that one component of the signal is protein kinase C beta (PKC beta). This molecule is up-regulated in CLL and is involved in determining the signaling strength of the receptor. It has a double effect. It sends an anti-apoptotic message from the BCR so as to keep the CLL cell alive, but also limits the signaling strength of BCR crosslinking. This is important, because a strong signal from the BCR triggers apoptosis in B cells as part of the mechanism to stop the body making antibodies against itself..
It has been shown in the TCL1 mouse model that deleting the gene for PCK beta prevents full blown CLL developing in the animal. As an aside, when we considering how ZAP-70 works in CLL we noted that it does not itself transmit the signal, that is the role of syk, but it enhances syk signaling. It appears that it does this by recruiting PCK beta into lipid rafts.
The new information concerns vascular endothelial growth factor. When I was working with Steve Devereux at Kings, we had some evidence that VEGF is concerned with the formation of proliferation centers in the lymph nodes and we actually proposed a trial of bevacizumab in CLL to the British CLL trials organization. It was turned down, which was just as well, since trials in Germany and at the Mayo have shown no benefit for this drug. The Mayo has shown that VEGF enhances survival of CLL cells in the test tube by modulating components of the apoptosis machinery and that VEGF levels correlate with response to chemoimmunotherapy.
This essay in Blood refers to a new British paper in the same issue by Abrams et al. VEGF levels are higher in patients with unmutated IGHV genes. The interaction between CLL cells and VEGF seems to occur in CD38 positive cells and there may be a role in limiting CLL cell migration away from proliferation centers. Abrams et al propose a mechanism by which VEGF optimizes the |BCR/PCK beta signal so as to prevent it triggering pro-apoptotic signals and enhance anti-apoptotic signals.