Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Chronic Lymphocytic Leukemia, Normal B and T Cells

ZAP-70 is expressed by normal and malignant human B-cell subsets of different maturational stage


ZAP-70 tyrosine kinase is involved in signalling pathways following T-cell receptor stimulation and was originally described only in T cells and natural killer cells. ZAP-70 expression has been reported in normal mouse B lineage cells and in human malignant B lymphocytes, mainly in chronic lymphocytic leukemia (CLL) where it correlates with clinical outcome. We analyzed several B-cell lines and ex vivo malignant B cells, ranging from acute lymphoblastic leukemia to multiple myeloma and reflecting different stages of B-cell differentiation, and they showed ZAP-70 expression regardless their maturation stage. We then analyzed by Western blot and flow cytometry different human normal B-lymphocyte subpopulations: naïve, germinal center and memory B cells from tonsils, CD19+ CD5+ cells from cord blood and CD19+ lymphocytes from peripheral blood. All expressed ZAP-70 protein, though at different levels depending on their differentiation, activation and tissue localization. In addition, ZAP-70 expression levels could be modulated following stimulation via the B-cell receptor. These findings implicate a potential role of ZAP-70 in the signalling pathway of B lymphocytes at different maturational stages, indicate that ZAP-70 expression is not a CLL-specific feature among B-cell malignancies and suggest that the absence of ZAP-70 rather than its presence should be considered abnormal for malignant B lymphocytes.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4


  1. Chan AC, Iwashima M, Turck CW, Weiss A . ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell 1992; 71: 649–662.

    Article  CAS  Google Scholar 

  2. Law CL, Sidorenko SP, Chandran KA, Draves KE, Chan AC, Weiss A et al. Molecular cloning of human Syk. A B cell protein-tyrosine kinase associated with the surface immunoglobulin M-B cell receptor complex. J Biol Chem 1994; 269: 12310–12319.

    CAS  PubMed  Google Scholar 

  3. Chan AC, van Oers NS, Tran A, Turka L, Law CL, Ryan JC et al. Differential expression of ZAP-70 and Syk protein tyrosine kinases, and the role of this family of protein tyrosine kinases in TCR signaling. J Immunol 1994; 152: 4758–4766.

    CAS  PubMed  Google Scholar 

  4. 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, [E-pub 2003 Feb 4920].

    Article  CAS  Google Scholar 

  5. 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, E-pub 2002 Aug 4608.

    Article  CAS  Google Scholar 

  6. 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.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Chen L, Apgar J, Huynh L, Dicker F, Giago-McGahan T, Rassenti L et al. ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. Blood 2005; 105: 2036–2041.

    Article  CAS  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. Schweighoffer E, Vanes L, Mathiot A, Nakamura T, Tybulewicz VL . Unexpected requirement for ZAP-70 in pre-B cell development and allelic exclusion. Immunity 2003; 18: 523–533.

    Article  CAS  Google Scholar 

  11. Nolz JC, Tschumper RC, Pittner BT, Darce JR, Kay NE, Jelinek DF . ZAP-70 is expressed by a subset of normal human B-lymphocytes displaying an activated phenotype. Leukemia 2005; 19: 1018–1024.

    Article  CAS  Google Scholar 

  12. Carreras J, Villamor N, Colomo L, Moreno C, Ramon y CS, Crespo M et al. Immunohistochemical analysis of ZAP-70 expression in B-cell lymphoid neoplasms. J Pathol 2005; 205: 507–513.

    Article  CAS  Google Scholar 

  13. Sup SJ, Domiati-Saad R, Kelley TW, Steinle R, Zhao X, Hsi ED . ZAP-70 expression in B-cell hematologic malignancy is not limited to CLL/SLL. Am J Clin Pathol 2004; 122: 582–587.

    Article  CAS  Google Scholar 

  14. Admirand JH, Rassidakis GZ, Abruzzo LV, Valbuena JR, Jones D, Medeiros LJ . Immunohistochemical detection of ZAP-70 in 341 cases of non-Hodgkin and Hodgkin lymphoma. Mod Pathol 2004; 17: 954–961.

    Article  CAS  Google Scholar 

  15. Guillaume N, Alleaume C, Munfus D, Capiod JC, Touati G, Pautard B et al. ZAP-70 tyrosine kinase is constitutively expressed and phosphorylated in B-lineage acute lymphoblastic leukemia cells. Haematologica 2005; 90: 899–905.

    CAS  PubMed  Google Scholar 

  16. Kantor A . A new nomenclature for B cells. Immunol Today 1991; 12: 388.

    Article  CAS  Google Scholar 

  17. Ghia P, Boussiotis VA, Schultze JL, Cardoso AA, Dorfman DM, Gribben JG et al. Unbalanced expression of bcl-2 family proteins in follicular lymphoma: contribution of CD40 signaling in promoting survival. Blood 1998; 91: 244–251.

    CAS  PubMed  Google Scholar 

  18. 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.

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Alessio M, De Monte L, Scirea A, Gruarin P, Tandon NN, Sitia R . Synthesis, processing, and intracellular transport of CD36 during monocytic differentiation. J Biol Chem 1996; 271: 1770–1775.

    Article  CAS  Google Scholar 

  21. Sahuquillo AG, Roumier A, Teixeiro E, Bragado R, Alarcon B . T cell receptor (TCR) engagement in apoptosis-defective, but interleukin 2 (IL-2)-producing, T cells results in impaired ZAP70/CD3-zeta association. J Exp Med 1998; 187: 1179–1192.

    Article  CAS  Google Scholar 

  22. Durig J, Nuckel H, Cremer M, Fuhrer A, Halfmeyer K, Fandrey J et al. ZAP-70 expression is a prognostic factor in chronic lymphocytic leukemia. Leukemia 2003; 17: 2426–2434.

    Article  CAS  Google Scholar 

  23. Corcoran M, Parker A, Orchard J, Davis Z, Wirtz M, Schmitz OJ et al. ZAP-70 methylation status is associated with ZAP-70 expression status in chronic lymphocytic leukemia. Haematologica 2005; 90: 1078–1088.

    CAS  PubMed  Google Scholar 

  24. Damle RN, Ghiotto F, Valetto A, Albesiano E, Fais F, Yan XJ et al. B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes. Blood 2002; 99: 4087–4093.

    Article  CAS  Google Scholar 

  25. Lanham S, Hamblin T, Oscier D, Ibbotson R, Stevenson F, Packham G . Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia. Blood 2003; 101: 1087–1093, [Eub 2002 Sep 1026].

    Article  CAS  Google Scholar 

  26. Scielzo C, Ghia P, Conti A, Bachi A, Guida G, Geuna M et al. HS1 protein is differentially expressed in chronic lymphocytic leukemia patient subsets with good or poor prognoses. J Clin Invest 2005; 115: 1644–1650.

    Article  CAS  Google Scholar 

Download references


CS is a recipient of a scholarship from FIRC, Milano. We are grateful to Ms Rose Mary Carletti for her precious technical assistance and to Dr Michela Frenquelli for her continuous support in the lab work. We are indebted with Alessandro Ambrosi, Eliana La Ferrara e Giuseppe Guida for their precious advice on statistical analysis. This work was supported in part by Associazione Italiana per la Ricerca sul Cancro (AIRC), Progetto Oncologia CNR-MIUR, MURST 40%, the CLL Global Research Foundation, Ministero della Sanità (R.F.2002, no. 183), Fondazione CARIPLO and MIUR-Firb (RBNE01LNX7-006).

Author information

Authors and Affiliations


Corresponding author

Correspondence to P Ghia.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Scielzo, C., Camporeale, A., Geuna, M. et al. ZAP-70 is expressed by normal and malignant human B-cell subsets of different maturational stage. Leukemia 20, 689–695 (2006).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • ZAP-70
  • B lymphocytes
  • B-lymphoid malignancies
  • chronic lymphocytic leukemia

This article is cited by


Quick links