Antigen receptor signaling in CLL—is the line dead?

B-cell chronic lymphocytic leukemia (CLL) can be segregated into 2 subtypes based upon the nature of the expressed immunoglobulin (Ig) genes. Leukemia cells that use unmutated Ig more often express CD38 and are associated with a higher tendency toward disease progression than are CLL cells that express mutated Ig. Lanham and colleagues (page 1087) presents evidence that CLL cells that have unmutated Ig are more likely than CLL cells with mutated Ig to undergo tyrosine phosphorylation of cytosolic proteins (a mark of signal transduction) upon ligation of the B-cell receptor (BCR) for antigen. These observations are in agreement with those of others (Chen et al, Blood. 2002;100:4609-4614) and suggest that the 2 subtypes of leukemia differ in their capacity to respond to the crosslinking of their surface Ig by antigen. Not unexpectedly, the association between mutational status and signal transduction capacity was not absolute but probably reflects other biologic differences between the 2 leukemia subtypes.

One likely candidate for this is ZAP-70, a protein tyrosine kinase required for receptor signaling in T cells that often is expressed by CLL cells with unmutated Ig, but generally not by CLL with mutated Ig or normal B cells (Rosenwald et al, J Exp Med. 2001;194:1639-1647). The study of Chen et al found that the capacity to signal via the BCR for antigen was associated most closely with the expression of this kinase, even in unusual cases that expressed ZAP-70 but used mutated Ig receptors. Conceivably, the difference in the capacity of the leukemia cells to be stimulated by ligation of their BCR relates to differences in the noted clinical behavior of these 2 subtypes of CLL. If so, then analyses of the receptor signaling capacity might provide for a more reliable prognostic indicator than expression of CD38, Ig mutational status, or other features found differentially expressed by the 2 subtypes of this leukemia.