It is now very clear that signaling through the B-cell receptor (BCR) is extremely important in determining how active CLL is. My original observation that mutated VH genes predict a more benign version of the disease has turned out to be one of the more important discoveries in the history of CLL, giving rise to the realization that perhaps 30% of cases have BCRs that belong to a limited set of stereotypes and therefore many CLLs derive from B cells involved in the same immune response, and, perhaps more significant for patients, the signaling pathways reveal targets for therapy. Already we have trials of agents that block these pathways, like fostanatinib, which blocks spleen tyrosine kinase (syk) activity and PC-32765, which blocks Bruton tyrosine kinase (Btk) activity.
Disease activity in CLL takes place in the tissues, not the blood, and it has been shown that signaling through the BCR cuases the up-regulation and secretion of the chemokines CCL3 and CCL4. These chemokines were previously called macrophage inflammatory proteins 1 alfa and 1 beta (MIP-1 alfa and beta) and function by attracting macrophages and lymphocytes.
There are tests for signaling through the BCR, but they are cumbersome and only suitable for research laboratories. As is well known, VH mutations are little more tricky than the ordinary lab is used to and various people have proposed surrogates. CD38 turned out to be an independent prognostic marker in its own right and ZAP-70 has proved impossible to standardize. The possibility arises that CCL3, which is secreted in large amounts when BCR signaling takes place might be an even more useful prognostic marker than VH genes. Although most mutated VH genes give rise to a BCR that will not signal and unmutated VH genes give rise to a BCR that does, the correlation is not complete and it may well be that it is the signaling that matters not the structure of the BCR. Since it is secreted, CCL could be measured in the blood by a simple ELISA that even a biochemistry lab could do.
To this end the group at MDACC have developed an ELISA to measure CCL3 in the blood of 351 patients with CLL. They have analyzed high levels of CCL3 as a prognostic marker (end point: time to first treatment) in a multivariate study. Interestingly, the prognostic factors that were statistically significant clinical stage, FISH for chromosomal abnormalities, CD38 and CCL3 levels. Both VH mutations and ZAP-70 were squeezed out by this analysis which suggests that it is the signaling rather than the structure of the BCR that matters.
Of course knowing the VH sequence has other value, since it appears that certain stereotypes have their own individual characteristic types of progression, but this is a simple and cheap test that could be a surrogate for VH testing if it can be reproduced by another study.