The mutational status of immunoglobulin heavy-chain variable-region (IgV_H ) genes in the leukemic cells of chronic lymphocytic leukemia (CLL) is an important prognostic factor in the disease. We investigated whether the expression of ZAP-70 by CLL cells correlated with the IgV_H mutational status, disease progression, and survival.

The expression of ZAP-70 was analyzed in T-cell and B-cell lines and in peripheral-blood samples from 56 patients with CLL with the use of flow cytometry, Western blotting, and immunohistochemistry. The results were correlated with the IgV_H mutational status and clinical outcome.

ZAP-70 was detected by flow-cytometric analysis in cells of T-cell lineage and in leukemic cells from 32 of 56 patients with CLL. In all patients in whom at least 20 percent of the leukemic cells were positive for ZAP-70, IgV_H was unmutated, whereas IgV_H mutations were found in 21 of 24 patients in whom less than 20 percent of the leukemic cells were positive for ZAP-70 (P<0.001). Concordant results were obtained when ZAP-70 expression was assessed by immunohistochemistry or Western blotting. The level of ZAP-70 expression did not change over time (median, 37 months) in sequential samples from 30 patients with CLL. Patients with Binet stage A CLL who had at least 20 percent ZAP-70–positive leukemic cells had more rapid progression and poorer survival than those with less than 20 percent ZAP-70–positive cells.

Among patients with CLL, expression of ZAP-70, as detected by flow-cytometric analysis, correlated with IgV_H mutational status, disease progression, and survival.