DIMINISHED TCR SIGNALING IN CUTANEOUS T-CELL LYMPHOMA IS ASSOCIATED WITH DECREASED ACTIVITIES OF ZAP70, SYK AND MEMBRANE-ASSOCIATED CSK

Malignant cells of patients with cutaneous T cell lymphoma (CTCL) are of monoclonal origin and of the CD4(+)/CD45RO(+) subset. Since unlike their normal counterparts, triggering of their TCR/CD3 in vitro elicit s only a weak mitogenic response, we set out to determine which of the signal transduction molecules initiated by anti-CD3 epsilon antibodie s are affected in neoplastic cells. The results obtained from analysis of tumor cells from four patients show a general reduction in basal a nd induced tyrosine phosphorylation of a wide range of signaling prote ins. Furthermore, the function of members from distinct families of pr otein tyrosine kinases was altered in neoplastic cells. The enzymatic activity of the membrane-bound fraction of Csk was suppressed, and its association with other cellular proteins was altered. There was a dec line in the amount and activity of Syk, and a slight decrease in the s pecific activity of Lck kinases. Zap70 tyrosyl phosphorylation was red uced or undetectable and the kinase associated weakly, or not at all, with the TCR zeta chain. We propose that dampened TCR-triggered respon ses in CTCL are caused by suppression of an array of effector molecule s required for coupling cell surface receptors to early and late signa ling events.