Skip to main content

Thank you for visiting nature.com. 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.

  • Original Manuscript
  • Published:

Chronic Lymphocytic Leukemia and Normal B-Cells

ZAP-70 is expressed by a subset of normal human B-lymphocytes displaying an activated phenotype

Leukemia volume 19, pages 1018–1024 (2005)Cite this article

Abstract

The Syk family tyrosine kinase ZAP-70 is essential for normal T-cell development and signaling. Recently, leukemic cells from some patients with B-cell chronic lymphocytic leukemia (B-CLL) were shown to express ZAP-70. Owing to the prognostic value of B-CLL ZAP-70 expression, this phenotype may reflect intrinsic biological differences between the two subsets of disease. However, it remains unclear whether CLL-B cells aberrantly acquire ZAP-70 expression during the transformation process or whether ZAP-70 may be expressed under certain conditions in normal human B-lymphocytes. To discriminate between these two possibilities, we assessed ZAP-70 expression in normal human B-lymphocytes. Our data demonstrate that ZAP-70 is expressed in a subpopulation of tonsillar and splenic normal B-lymphocytes that express an activated phenotype. Furthermore, ZAP-70 expression can be induced in vitro upon stimulation of blood and tonsillar B cells. Finally, we show that phosphorylation of ZAP-70 occurs in tonsillar B cells with stimulation through the B-cell receptor. These results provide new insight into normal human B-cell biology as well as provide clues about the transformed cell in B-CLL.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. van Oers NSC, Weiss A . The Syk/ZAP-70 protein tyrosine kinase connection to antigen receptor signalling processes. Semin Immunol 1995; 7: 227–236.

    Article  CAS  PubMed  Google Scholar 

  2. 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  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.

    Article  CAS  PubMed  Google Scholar 

  5. 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  PubMed  Google Scholar 

  6. Bosch F, Villamor N . ZAP-70 expression in chronic lymphocytic leukemia: a new parameter for an old disease. Haematologica 2003; 88: 724–726.

    PubMed  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  PubMed  Google Scholar 

  8. 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  PubMed  PubMed Central  Google Scholar 

  9. 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  PubMed  Google Scholar 

  10. 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.

    CAS  PubMed  Google Scholar 

  11. 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.

    CAS  PubMed  Google Scholar 

  12. Krober A, Seiler T, Benner A, Bullinger L, Bruckle E, Lichter P et al. V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 2002; 100: 1410–1416.

    CAS  PubMed  Google Scholar 

  13. Oscier DG, Gardiner AC, Mould SJ, Glide S, Davis ZA, Ibbotson RE et al. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent of prognostic factors. Blood 2002; 100: 1177–1184.

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Meade J, Tybulewicz VL, Turner M . The tyrosine kinase Syk is required for light chain isotype exclusion but dispensable for the negative selection of B cells. Eur J Immunol 2004; 34: 1102–1110.

    Article  CAS  PubMed  Google Scholar 

  17. Chen L, Widhopft 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.

    Article  CAS  PubMed  Google Scholar 

  18. 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  PubMed  Google Scholar 

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

    Article  Google Scholar 

  20. Jelinek DF, Tschumper RC, Stolovitzky GA, Iturria SJ, Tu Y, Lepre J et al. Identification of a global gene expression signature of B-chronic lymphocytic leukemia. Mol Cancer Res 2003; 1: 346–361.

    CAS  PubMed  Google Scholar 

  21. Bernasconi NL, Traggiai E, Lanzavecchia A . Maintenance of serological memory by polyclonal activation of human memory B cells. Science 2002; 298: 2199–2202.

    Article  CAS  PubMed  Google Scholar 

  22. Walters DK, French JD, Arendt BK, Jelinek DF . Atypical expression of ErbB3 in myeloma cells: cross-talk between ErbB3 and the interferon-α signaling complex. Oncogene 2003; 22: 3598–3607.

    Article  CAS  PubMed  Google Scholar 

  23. Williams BL, Schreiber KL, Zhang W, Wange RL, Samelson LE, Leibson PJ et al. Genetic evidence for differential coupling of Syk family kinases to the T-Cell receptor: reconstitution studies in a ZAP-70 deficient Jurkat T-cell line. Mol Cell Biol 1998; 18: 1388–1399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu YJ, Arpin C . Germinal center development. Immunol Rev 1997; 156: 111–126.

    Article  CAS  PubMed  Google Scholar 

  25. Liu YJ, Arpin C, de Bouteiller O, Guret C, Banchereau J, Martinez-Valdez H et al. Sequential triggering of apoptosis, somatic mutation, and isotype switch during germinal center development. Semin Immunol 1996; 8: 169–177.

    Article  CAS  PubMed  Google Scholar 

  26. 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  PubMed  Google Scholar 

  27. Kong GH, Bu JY, Kurosaki T, Shaw AS, Chan AC . Reconstitution of Syk function by the ZAP-70 protein tyrosine kinase. Immunity 1995; 5: 485–492.

    Article  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. Zupo S, Isnardi L, Megna M, Massara R, Malavasi F, Dono M et al. CD38 expression distinguishes two groups of B-cell chronic lymphocytic leukemias with different responses to anti-IgM antibodies and propensity to apoptosis. Blood 1996; 88: 1365–1374.

    CAS  PubMed  Google Scholar 

  31. Latour S, Veillette A . Proximal protein tyrosine kinases in immunoreceptor signaling. Curr Opin Immunol 2001; 13: 299–306.

    Article  CAS  PubMed  Google Scholar 

  32. Kolanus W, Romeo C, Seed B . T cell activation by clustered tyrosine kinases. Cell 1993; 74: 171–183.

    Article  CAS  PubMed  Google Scholar 

  33. Futterer K, Wong J, Grucza RA, Chan AC, Waksman G . Structural basis for Syk tyrosine kinase ubiquity in signal transduction pathways revealed by the crystal structure of its regulatory SH2 domains bound to a dually phosphorylated ITAM peptide. J Mol Biol 1998; 281: 523–537.

    Article  CAS  PubMed  Google Scholar 

  34. Steinberg M, Adjali O, Swainson L, Merida P, Di Bartolo V, Pelletier L et al. T-cell receptor-induced phosphorylation of the zeta chain is efficiently promoted by ZAP-70 but not Syk. Blood 2004; 104: 760–767.

    Article  CAS  PubMed  Google Scholar 

  35. Latour S, Chow LML, Veillette A . Differential intrinsic enzymatic activity of Syk and ZAP-70 protein-tyrosine kinases. J Biol Chem 1996; 271: 22782–22790.

    Article  CAS  PubMed  Google Scholar 

  36. Thien CB, Bowtell DD, Langdon WY . Perturbed regulation of ZAP-70 and sustained tyrosine phosphorylation of LAT and SLP-76 in c-Cbl deficient thymocytes. J Immunol 1999; 162: 7133–7139.

    CAS  PubMed  Google Scholar 

  37. Yasuda T, Maeda A, Kurosaki M, Tezuka T, Hironaka K, Yamamoto T et al. Cbl suppresses B cell receptor-mediated phospholipase C (PLC) gamma2 activation by regulating B cell linker protein-PLC-gamma2 binding. J Exp Med 2000; 191: 641–650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by National Institute of Health Training Grant 5-T32-HL67742 (BTP).

Author information

Authors and Affiliations

  1. Department of Immunology, Mayo Clinic College of Medicine, Mayo Graduate School, Rochester, MN, USA

    J C Nolz, R C Tschumper, B T Pittner, J R Darce & D F Jelinek

  2. Department of Internal Medicine, Division of Hematology, Mayo Clinic College of Medicine, Mayo Graduate School, Rochester, MN, USA

    N E Kay

Authors
  1. J C Nolz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R C Tschumper
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B T Pittner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J R Darce
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N E Kay
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D F Jelinek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D F Jelinek.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nolz, J., Tschumper, R., Pittner, B. et al. ZAP-70 is expressed by a subset of normal human B-lymphocytes displaying an activated phenotype. Leukemia 19, 1018–1024 (2005). https://doi.org/10.1038/sj.leu.2403726

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403726

Keywords

This article is cited by

Search

Advanced search

Quick links