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Clinical Chemistry 53: 1757-1766, 2007. First published August 16, 2007; 10.1373/clinchem.2007.089326
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(Clinical Chemistry. 2007;53:1757-1766.)
© 2007 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Quantification of ZAP70 mRNA in B Cells by Real-Time PCR Is a Powerful Prognostic Factor in Chronic Lymphocytic Leukemia

Basile Stamatopoulos1,a, Nathalie Meuleman1, Benjamin Haibe-Kains2,3, Hughes Duvillier1, Martine Massy1, Philippe Martiat1, Dominique Bron1 and Laurence Lagneaux1

1 Laboratory of Experimental Hematology, 2 Functional Genomics and Translational Research Unit, Faculty of Medicine, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.
3 Machine Learning Group, Faculty of Sciences, Université Libre de Bruxelles (ULB), Brussels, Belgium.

aAddress correspondence to this author at: Université Libre de Bruxelles, Institut Jules Bordet, Laboratoire d’Hématologie Expérimentale, Boulevard de Waterloo no. 121-1000 Bruxelles, Belgium. Fax 32-0-2-541-3453; e-mail bstamato{at}ulb.ac.be.

Background: Chronic lymphocytic leukemia (CLL) is heterogeneous with respect to prognosis and clinical outcome. The mutational status of the immunoglobulin variable heavy chain region (IGHV) has been used to classify patients into 2 groups in terms of overall survival (OS) and clinical characteristics, but the labor-intensive nature and the cost of this time-consuming analysis has prompted investigations of surrogate markers.

Methods: We developed a standardized quantitative real-time reverse transcription-PCR (qPCR) method to measure zeta-chain (TCR)-associated protein kinase (ZAP70) mRNA in purified CD19+ cells. We evaluated this and other methods (flow cytometry analyses of ZAP70 and CD38 proteins and qPCR analysis of lipoprotein lipase mRNA) in a cohort of 108 patients (median follow-up, 82 months) to evaluate any associations with IGHV mutational status, OS, and treatment-free survival (TFS).

Results: The association between qPCR-measured ZAP70 and IGHV mutational status was statistically significant [{chi}2 (1) = 50.95; P <0.0001], and the value of Cramer’s V statistic (0.72) indicated a very strong relation. This method also demonstrated sensitivity, specificity, and positive and negative predictive values of 87.8%, 85.7%, 87.5%, and 86%, respectively. ZAP70 expression was significantly associated with OS (P = 0.0021) and TFS (P <0.0001). ZAP70+ patients had significantly shorter median TFS (24 months) than ZAP70– patients (157 months) (P <0.0001). Moreover, qPCR-measured ZAP70 expression has greater prognostic power than IGHV mutational status and the other prognostic markers tested.

Conclusions: ZAP70 mRNA quantification via qPCR is a strong surrogate marker of IGHV mutational status and a powerful prognostic factor.




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