Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia

The mutational status of tumor immunoglobulin V-H genes is providing a powerful prognostic marker for chronic lymphocytic leukemia (CLL), with patients having tumors expressing unmutated VH genes being in a less favorable subset. However, the biologic differences correlating with V-H gene status that could determine the clinical course of the disease are unknown. Here we show that differing responses to IgM ligation are closely associated with V-H gene status. Specifically, 80% of cases with unmutated V-H genes showed increased global tyrosine phosphorylation following IgM ligation, whereas only 20% of samples with mutated V-H genes responded (P = .0002). There was also an association between response to IgM ligation and expression of CD38 (P = .015). The Syk kinase, critical for transducing B-cell receptor (BCR)derived signals, was constitutively present in all CLL samples, and there was a perfect association between global phosphorylation and induction of phosphorylation/activation of Syk. Nonresponsiveness to anti-IgM could be circumvented by ligation of IgD (110 of 15 samples tested) or the BCR-associated molecule CD79alpha (12 of 15 samples tested). These results suggest that multiple mechanisms underlie non responsiveness to anti-IgM in CLL and that retained responsiveness to anti-IgM contributes to the poor prognosis associated with the unmutated subset of CLL. The prognostic power of the in vitro response to IgM ligation remains to be determined in a large series, but the simple technology involved may present an alternative or additional test for predicting clinical course. (C) 2003 by The American Society of Hematology.