Abstract
B-cell chronic lymphocytic leukemia (B-CLL) is a heterogenous disease with a highly variable clinical course. Recent studies have shown that expression of the protein tyrosine kinase ZAP-70 may serve as a prognostic marker in B-CLL. Employing a semiquantitative RT-PCR assay, we examined purified leukemia B cells of 39 CLL patients for the expression of ZAP-70 mRNA transcripts. Significant ZAP-70 mRNA levels exceeding those found in control samples with 5% T cells were detected in 36% of the CLL cases. Patients in the ZAP-70 positive cohort were characterized by an unfavorable clinical course with a significantly shorter progression-free survival as compared to the ZAP-70-negative patients (64%). These results were confirmed by flow-cytometric analysis of the ZAP-70 protein, and expanded to a larger patient cohort (n=67). A combined statistical analysis of 79 patients showed that the two patient subgroups also differed with regard to overall survival and a panel of known clinical prognostic factors including LDH, thymidine kinase serum levels and expression of the CD38 surface antigen by the leukemic cell clone. The level of ZAP-70 expression did not change over time in the majority of patients where sequential samples were available for analysis.
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References
Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS . Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46: 219–234.
Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981; 48: 198–206.
Binet JL . Prognostic factors in chronic lymphocytic leukaemia. Haematologica 1999; 84: 96–97.
Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840–1847.
Del Poeta G, Maurillo L, Venditti A, Buccisano F, Epiceno AM, Capelli G et al. Clinical significance of CD38 expression in chronic lymphocytic leukemia. Blood 2001; 98: 2633–2639.
Dürig J, Naschar M, Schmücker U, Renzing-Köhler K, Hölter T, Hüttmann A et al. CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia. Leukemia 2002; 16: 30–35.
Dürig J, Nückel H, Hüttmann A, Kruse E, Hölter T, Halfmeyer K et al. Expression of ribosomal and translation-associated genes is correlated with a favorable clinical course in chronic lymphocytic leukemia. Blood 2003; 101: 2748–2755.
Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK . Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94: 1848–1854.
Hamblin TJ, Orchard JA, Ibbotson RE, Davis Z, Thomas PW, Stevenson FK et al. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 2002; 99: 1023–1029.
Ibrahim S, Keating M, Do KA, O'Brien S, Huh YO, Jilani I et al. CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. Blood 2001; 98: 181–186.
Stilgenbauer S, Lichter P, Döhner H . Genetic features of B-cell chronic lymphocytic leukemia. Rev Clin Exp Hematol 2000; 4: 48–72.
Stilgenbauer S, Bullinger L, Lichter P, Döhner H . Genetics of chronic lymphocytic leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course. Leukemia 2002; 16: 993–1007.
Thunberg U, Tobin G, Johnson A, Soderberg O, Padyukov L, Hultdin M et al. Polymorphism in the P2X7 receptor gene and survival in chronic lymphocytic leukaemia. Lancet 2002; 360: 1935–1939.
Wiestner A, Rosenwald A, Barry TS, Wright G, Davis RE, Henrickson SE et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 2003; 101: 4944–4951.
Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, Yu X et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 2001; 194: 1639–1647.
Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87: 4990–4997.
Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 2003; 348: 1764–1775.
Rosenwald A, Staudt LM . Clinical translation of gene expression profiling in lymphomas and leukemias. Semin Oncol 2002; 29: 258–263.
Lin K, Sherrington PD, Dennis M, Matrai Z, Cawley JC, Pettitt AR . Relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation in chronic lymphocytic leukemia. Blood 2002; 100: 1404–1409.
Hamblin TJ, Orchard JA, Gardiner A, Oscier DG, Davis Z, Stevenson FK . Immunoglobulin V genes and CD38 expression in CLL. Blood 2000; 95: 2455–2457.
Chen L, Widhopf G, Huynh L, Rassenti L, Rai KR, Weiss A et al. Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. Blood 2002; 100: 4609–4614.
Deaglio S, Zubiaur M, Gregorini A, Bottarel F, Ausiello CM, Dianzani U et al. Human CD38 and CD16 are functionally dependent and physically associated in natural killer cells. Blood 2002; 99: 2490–2498.
Zubiaur M, Fernandez O, Ferrero E, Salmeron J, Malissen B, Malavasi F et al. CD38 is associated with lipid rafts and upon receptor stimulation leads to Akt/protein kinase B and Erk activation in the absence of the CD3-zeta immune receptor tyrosine-based activation motifs. J Biol Chem 2002; 277: 13–22.
Acknowledgements
We thank Ute Schmücker for expert technical assistence with flow cytometry and Brigitte Fischer for her help with compiling patient data.
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Dürig, J., Nückel, H., Cremer, M. et al. ZAP-70 expression is a prognostic factor in chronic lymphocytic leukemia. Leukemia 17, 2426–2434 (2003). https://doi.org/10.1038/sj.leu.2403147
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DOI: https://doi.org/10.1038/sj.leu.2403147
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