ZAP-70 Linked to Mutational Status, CLL Prognosis

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Volume 348:1764-1775 May 1, 2003 Number 18

ZAP-70 Expression as a Surrogate for Immunoglobulin-Variable-Region

Mutations in Chronic Lymphocytic Leukemia

Marta Crespo, B.S., Francesc Bosch, M.D., Neus Villamor, M.D.,

Beatriz Bellosillo, Ph.D., Dolors Colomer, Ph.D., María Rozman, M.D.,

Silvia Marcé, B.S., López-Guillermo, M.D., Elies Campo, M.D.,

and Emili Montserrat, M.D.

ABSTRACT

Background:

The mutational status of immunoglobulin heavy-chain variable-region

(IgVH) 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 IgVH mutational status, disease progression, and survival.

Methods:

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 IgVH mutational status and clinical

outcome.

Results:

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, IgVH was unmutated, whereas IgVH 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.

Conclusions:

Among patients with CLL, expression of ZAP-70, as detected by flow-

cytometric analysis, correlated with IgVH mutational status, disease

progression, and survival.

Source Information:

From the Department of Hematology (M.C., F.B., A.L.-G., E.M.) and the

Hematopathology Unit (N.V., B.B., D.C., M.R., S.M., E.C.), Institut

d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic,

Barcelona, Spain.