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Quantification of ZAP-70 mRNA by real-time PCR is a prognostic factor in chronic lymphocytic leukemia

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Abstract

Background

Chronic lymphocytic leukemia (CLL) is heterogeneous with respect to prognosis and clinical outcome. Mutational status of immunoglobulin heavy chain variable region (IGHV) appears to be a particularly strong prognostic marker, but it is difficult to perform in a routine clinical laboratory. ζ-chain-associated protein kinase 70 kDa (ZAP-70) protein detected by flow cytometry is a strong surrogate marker of IGHV mutational status; however, it suffers from the lack of standardization.

Methods

We investigated whether ZAP-70 mRNA expression level can be a prognostic factor in CLL. Real-time quantitative polymerase chain reaction was used to analyze ZAP-70 mRNA expression from 102 CLL patients.

Results

The expression of ZAP-70 mRNA was significantly associated with Binet stage (P < 0.001), lactate dehydrogenase (P = 0.003), ZAP-70 protein (P = 0.018), IGHV mutational status (P = 0.038), and cytogenetic abnormality of del(17p13) or del(11q22.3) (P = 0.037) in CLL patients. According to receiver operating characteristic curve analysis for ZAP-70 mRNA and ZAP-70 protein, positive ZAP-70 mRNA (P = 0.006) was an adverse factor in determining the treatment free survival (TFS). In a multivariate Cox analysis of TFS, ZAP-70 mRNA is not ideal as an independent prognostic factor. However, ZAP-70 mRNA was statistically significant in predicting treatment response.

Conclusion

This study demonstrated the value of determination of ZAP-70 mRNA in providing useful prognostic information in CLL patients. However, ZAP-70 mRNA is not an independent prognostic factor.

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References

  • Antic D, Mihaljevic B, Cokic V, Fekete MD, Djurasevic TK, Pavlovic S et al (2011) Patients with early stage chronic lymphocytic leukemia: new risk stratification based on molecular profiling. Leuk Lymphoma 52(7):1394–1397

    Article  PubMed  CAS  Google Scholar 

  • Best OG, Ibbotson RE, Parker AE, Davis ZA, Orchard JA, Oscier DG (2006) ZAP-70 by flow cytometry: a comparison of different antibodies, anticoagulants, and methods of analysis. Cytometry B Clin Cytom 70(4):235–241

    PubMed  CAS  Google Scholar 

  • Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J et al (1981) A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48(1):198–206

    Article  PubMed  CAS  Google Scholar 

  • Catherwood MA, Matthews C, Niblock R, Dobbin E, Morris TC, Alexander HD (2006) ZAP-70 mRNA quantification in B-cell chronic lymphocytic leukaemia. Eur J Haemato 76(4):294–298

    Article  CAS  Google Scholar 

  • Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O’Brien S et al (1996) National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 87(12):4990–4997

    PubMed  CAS  Google Scholar 

  • Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M et al (2003) ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 348(18):1764–1775

    Article  PubMed  CAS  Google Scholar 

  • Gibbs G, Bromidge T, Howe D, Hopkins J, Johnson S (2005) Comparison of flow cytometric methods for the measurement of ZAP-70 expression in a routine diagnostic laboratory. Clin Lab Haematol 27(4):258–266

    Article  PubMed  CAS  Google Scholar 

  • Hamblin T (2002) Chronic lymphocytic leukaemia: one disease or two? Ann Hematol 81(6):299–303

    Article  PubMed  CAS  Google Scholar 

  • Orchard JA, Ibbotson RE, Davis Z, Wiestner A, Rosenwald A, Thomas PW et al (2004) ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 363(9403):105–111

    Article  PubMed  CAS  Google Scholar 

  • Qiu HX, Xu W, Cao XS, Zhou M, Shen YF, Xu YL et al (2008) Cytogenetic characterisation in Chinese patients with chronic lymphocytic leukemia: a prospective, multicenter study on 143 cases analysed with interphase fluorescence in situ hybridisation. Leuk Lymphoma 49(10):1887–1892

    Article  PubMed  CAS  Google Scholar 

  • Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS (1975) Clinical staging of chronic lymphocytic leukemia. Blood 46(2):219–234

    PubMed  CAS  Google Scholar 

  • Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG et al (2004) ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 351(9):893–901

    Article  PubMed  CAS  Google Scholar 

  • Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, Yu X et al (2001) Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 194(11):1639–1647

    Article  PubMed  CAS  Google Scholar 

  • Shankey TV, Forman M, Scibelli P, Cobb J, Smith CM, Mills R et al (2006) An optimized whole blood method for flow cytometric measurement of ZAP-70 protein expression in chronic lymphocytic leukemia. Cytometry B Clin Cytom 70(4):259–269

    PubMed  Google Scholar 

  • Sheikholeslami MR, Jilani I, Keating M, Uyeji J, Chen K, Kantarjian H et al (2006) Variations in the detection of ZAP-70 in chronic lymphocytic leukemia: Comparison with IgV(H) mutation analysis. Cytometry B Clin Cytom 70(4):270–275

    PubMed  CAS  Google Scholar 

  • Stamatopoulos B, Meuleman N, Haibe-Kains B, Duvillier H, Massy M, Martiat P et al (2007) Quantification of ZAP70 mRNA in B cells by real-time PCR is a powerful prognostic factor in chronic lymphocytic leukemia. Clin Chem 53(10):1757–1766

    Article  PubMed  CAS  Google Scholar 

  • Tobin G, Rosenquist R (2005) Prognostic usage of V(H) gene mutation status and its surrogate markers and the role of antigen selection in chronic lymphocytic leukemia. Med Oncol 22(3):217–228

    Article  PubMed  CAS  Google Scholar 

  • Wang YH, Fan L, Xu W, Li JY (2011) Detection methods of ZAP-70 in chronic lymphocytic leukemia. Clin Exp Med (Epub ahead of print)

  • Xu W, Cao X, Miao KR, Qiao C, Wu YJ, Liu Q et al (2009a) Serum thymidine kinase 1 concentration in Chinese patients with chronic lymphocytic leukemia and its correlation with other prognostic factors. Int J Hematol 90(2):205–211

    Article  PubMed  CAS  Google Scholar 

  • Xu W, Li JY, Wu YJ, Yu H, Shen QD, Tian T et al (2009b) CD38 as a prognostic factor in Chinese patients with chronic lymphocytic leukaemia. Leuk Res 33(2):237–243

    Article  PubMed  CAS  Google Scholar 

  • Zanotti R, Ambrosetti A, Lestani M, Ghia P, Pattaro C, Remo A et al (2007) ZAP-70 expression, as detected by immunohistochemistry on bone marrow biopsies from early-phase CLL patients, is a strong adverse prognostic factor. Leukemia 21(1):102–109

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by National Natural Science Foundation of China (30871104, 30971296, 81170488), Natural Science Foundation of Jiangsu Province (BK2010584), Key Projects of Health Department of Jiangsu Province (K201108), Jiangsu Province’s Medical Elite Program (RC2011169), University Doctoral Foundation of the Ministry of Education of China (20093234110010), the Program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU, and Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Conflict of interest

We declare that we have no conflict of interest.

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Authors and Affiliations

  1. Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China

    Yin-Hua Wang, Zhi-Jian Zou, Ling Liu, Li-Na Zhang, Cheng Fang, Dan-Xia Zhu, Lei Fan, Jian-Yong Li & Wei Xu

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  1. Yin-Hua Wang
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  2. Zhi-Jian Zou
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  3. Ling Liu
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  4. Li-Na Zhang
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  5. Cheng Fang
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  6. Dan-Xia Zhu
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  7. Lei Fan
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  8. Jian-Yong Li
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  9. Wei Xu
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Corresponding author

Correspondence to Wei Xu.

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Wang, YH., Zou, ZJ., Liu, L. et al. Quantification of ZAP-70 mRNA by real-time PCR is a prognostic factor in chronic lymphocytic leukemia. J Cancer Res Clin Oncol 138, 1011–1017 (2012). https://doi.org/10.1007/s00432-012-1177-3

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  • DOI: https://doi.org/10.1007/s00432-012-1177-3

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