Skip to main content

Advertisement

SpringerLink
Log in

Bruton’s tyrosine kinase (Btk) is a useful marker for Hodgkin and B cell non-Hodgkin lymphoma

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Bruton’s tyrosine kinase (Btk) is a member of the Tec family of protein tyrosine kinases involved in B cell development and proliferation in neoplastic human lymphoid tissues. We used immunohistochemistry to evaluate a polyclonal anti-Btk antibody on formalin-fixed paraffin-embedded tissue blocks. The tested samples included normal lymphoid tissues, tissue samples of 395 different lymphomas and 14 malignant lymphoid cell lines. Btk was expressed more often in B cell lymphomas than in T cell lymphomas. This correlated well with the results obtained on B cell lymphoma cell lines, which strongly expressed Btk, in contrast to T cell lymphoma cell lines. More than 60 % of myelomas expressed Btk. Among Hodgkin lymphomas, the nodular lymphocyte predominant variant was more often positive (14/16) than the classical variant (6/27). Only one out of three Hodgkin lymphoma-derived cell lines showed a few atypical large cells expressing Btk. Btk represents a useful marker to identify B cell non-Hodgkin lymphomas. Furthermore, Btk might help to distinguish the nodular lymphocyte predominant variant of Hodgkin lymphomas from the classical form. Finally, in view of the recently discovered therapeutic potential of Btk inhibitors in lymphoma, we report the pattern of expression of Btk in a large collection of different types of lymphoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bao Y, Zheng J, Han C, Jin J, Han H, Liu Y, Lau YL, Tu W, Cao X (2012) Tyrosine kinase Btk is required for NK cell activation. J Biol Chem 287:23769–23778. doi:10.1074/jbc.M112.372425

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Block H, Zarbock A (2012) The role of the tec kinase Bruton’s tyrosine kinase (Btk) in leukocyte recruitment. Int Rev Immunol 31:104–118. doi:10.3109/08830185.2012.668982

    Article  CAS  PubMed  Google Scholar 

  3. Braeuninger A, Kuppers R, Strickler JG, Wacker HH, Rajewsky K, Hansmann ML (1997) Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells. Proc Natl Acad Sci U S A 94:9337–9342

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Brunner C, Muller B, Wirth T (2005) Bruton’s tyrosine kinase is involved in innate and adaptive immunity. Histol Histopathol 20:945–955

    CAS  PubMed  Google Scholar 

  5. Buggy JJ, Elias L (2012) Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. Int Rev Immunol 31:119–132. doi:10.3109/08830185.2012.664797

    Article  CAS  PubMed  Google Scholar 

  6. Burger JA (2014) Bruton’s tyrosine kinase (BTK) inhibitors in clinical trials. Curr Hematol Malig Rep 9:44–49. doi:10.1007/s11899-013-0188-8

    Article  PubMed  Google Scholar 

  7. de Weers M, Verschuren MC, Kraakman ME, Mensink RG, Schuurman RK, van Dongen JJ, Hendriks RW (1993) The Bruton’s tyrosine kinase gene is expressed throughout B cell differentiation, from early precursor B cell stages preceding immunoglobulin gene rearrangement up to mature B cell stages. Eur J Immunol 23:3109–3114. doi:10.1002/eji.1830231210

    Article  PubMed  Google Scholar 

  8. Gaspar HB, Ferrando M, Caragol I, Hernandez M, Bertran JM, De Gracia X, Lester T, Kinnon C, Ashton E, Espanol T (2000) Kinase mutant Btk results in atypical X-linked agammaglobulinaemia phenotype. Clin Exp Immunol 120:346–350

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Genevier HC, Hinshelwood S, Gaspar HB, Rigley KP, Brown D, Saeland S, Rousset F, Levinsky RJ, Callard RE, Kinnon C et al (1994) Expression of Bruton’s tyrosine kinase protein within the B cell lineage. Eur J Immunol 24:3100–3105. doi:10.1002/eji.1830241228

    Article  CAS  PubMed  Google Scholar 

  10. Hagemann T, Kwan SP (1993) A BstNI polymorphism at the BTK locus in Xq21.3-Xq22. Hum Mol Genet 2:2201

    Article  CAS  PubMed  Google Scholar 

  11. Hendriks RW, Kersseboom R (2006) Involvement of SLP-65 and Btk in tumor suppression and malignant transformation of pre-B cells. Semin Immunol 18:67–76. doi:10.1016/j.smim.2005.10.002

    Article  CAS  PubMed  Google Scholar 

  12. Jefferies CA, O’Neill LA (2004) Bruton’s tyrosine kinase (Btk)-the critical tyrosine kinase in LPS signalling? Immunol Lett 92:15–22. doi:10.1016/j.imlet.2003.11.017

    Article  CAS  PubMed  Google Scholar 

  13. Kersseboom R, Kil L, Flierman R, van der Zee M, Dingjan GM, Middendorp S, Maas A, Hendriks RW (2010) Constitutive activation of Bruton’s tyrosine kinase induces the formation of autoreactive IgM plasma cells. Eur J Immunol 40:2643–2654. doi:10.1002/eji.201040521

    Article  CAS  PubMed  Google Scholar 

  14. Kil LP, de Bruijn MJ, van Nimwegen M, Corneth OB, van Hamburg JP, Dingjan GM, Thaiss F, Rimmelzwaan GF, Elewaut D, Delsing D, van Loo PF, Hendriks RW (2012) Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice. Blood 119:3744–3756. doi:10.1182/blood-2011-12-397919

    Article  CAS  PubMed  Google Scholar 

  15. Marafioti T, Pozzobon M, Hansmann ML, Delsol G, Pileri SA, Mason DY (2004) Expression of intracellular signaling molecules in classical and lymphocyte predominance Hodgkin disease. Blood 103:188–193. doi:10.1182/blood-2003-05-1487

    Article  CAS  PubMed  Google Scholar 

  16. Ng YS, Wardemann H, Chelnis J, Cunningham-Rundles C, Meffre E (2004) Bruton’s tyrosine kinase is essential for human B cell tolerance. J Exp Med 200:927–934. doi:10.1084/jem.20040920

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Rushworth SA, Bowles KM, Barrera LN, Murray MY, Zaitseva L, MacEwan DJ (2013) BTK inhibitor ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities through NF-kappaB. Cell Signal 25:106–112. doi:10.1016/j.cellsig.2012.09.008

    Article  CAS  PubMed  Google Scholar 

  18. Sharma S, Orlowski G, Song W (2009) Btk regulates B cell receptor-mediated antigen processing and presentation by controlling actin cytoskeleton dynamics in B cells. J Immunol 182:329–339

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Smith CI, Baskin B, Humire-Greiff P, Zhou JN, Olsson PG, Maniar HS, Kjellen P, Lambris JD, Christensson B, Hammarstrom L et al (1994) Expression of Bruton’s agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. J Immunol 152:557–565

    CAS  PubMed  Google Scholar 

  20. Smith CI, Islam TC, Mattsson PT, Mohamed AJ, Nore BF, Vihinen M (2001) The Tec family of cytoplasmic tyrosine kinases: mammalian Btk, Bmx, Itk, Tec, Txk and homologs in other species. Bioessays 23:436–446. doi:10.1002/bies.1062

    Article  CAS  PubMed  Google Scholar 

  21. Takata M, Kurosaki T (1996) A role for Bruton’s tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2. J Exp Med 184:31–40

    Article  CAS  PubMed  Google Scholar 

  22. Tedoldi S, Paterson JC, Cordell J, Tan SY, Jones M, Manek S, Dei Tos AP, Roberton H, Masir N, Natkunam Y, Pileri SA, Facchetti F, Hansmann ML, Mason DY, Marafioti T (2006) Jaw1/LRMP, a germinal centre-associated marker for the immunohistological study of B-cell lymphomas. J Pathol 209:454–463. doi:10.1002/path.2002

    Article  CAS  PubMed  Google Scholar 

  23. Tsukada S, Rawlings DJ, Witte ON (1994) Role of Bruton’s tyrosine kinase in immunodeficiency. Curr Opin Immunol 6:623–630

    Article  CAS  PubMed  Google Scholar 

  24. Vargas L, Hamasy A, Nore BF, Smith CI (2013) Inhibitors of BTK and ITK: state of the new drugs for cancer, autoimmunity and inflammatory diseases. Scand J Immunol 78:130–139. doi:10.1111/sji.12069

    Article  CAS  PubMed  Google Scholar 

  25. Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F, Hammarstrom L, Kinnon C, Levinsky R, Bobrow M et al (1993) The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 361:226–233. doi:10.1038/361226a0

    Article  CAS  PubMed  Google Scholar 

  26. Woyach JA, Bojnik E, Ruppert AS, Stefanovski MR, Goettl VM, Smucker KA, Smith LL, Dubovsky JA, Towns WH, Macmurray J, Harrington BK, Davis ME, Gobessi S, Laurenti L, Chang BY, Buggy JJ, Efremov DG, Byrd JC, Johnson AJ (2014) Bruton’s tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood 123:1207–1213. doi:10.1182/blood-2013-07-515361

    Article  CAS  PubMed  Google Scholar 

  27. Wu H, Wang W, Liu F, Weisberg EL, Tian B, Chen Y, Li B, Wang A, Wang B, Zhao Z, McMillin DW, Hu C, Li H, Wang J, Liang Y, Buhrlage SJ, Liang J, Liu J, Yang G, Brown JR, Treon SP, Mitsiades CS, Griffin JD, Liu Q, Gray NS (2014) Discovery of a potent, covalent BTK inhibitor for B-cell lymphoma. ACS Chem Biol. doi:10.1021/cb4008524

    Google Scholar 

Download references

Acknowledgments

This work was fully supported by grants from the UCLH/UCL NIHR Comprehensive Biomedical Research Centre (TM). The authors would also like to thank the University Institute of Oncology of Asturias which is supported by Obra Social Cajastur, Asturias, Spain.

Conflict of interest

The authors declare that they have no conflict of interest in the research.

Author contributions

MT did the diagnosis of lymphomas, carried out the sample preparations, immunohistochemistry and data analyses and performed the coordination of the study. IF reviewed the stains, contributed with the data analyses and drafted the manuscript. LQ, JS and MP provided technical support and critically reviewed the manuscript. All authors read and approved the final manuscript.

Author information

Authors and Affiliations

  1. Department of Pathology, Hospital Universitario de Araba-Txagorritxu, Vitoria-Gasteiz, Spain

    Iván Fernández-Vega

  2. University Institute of Oncology of Asturias and Department of Functional Biology, University of Oviedo, Oviedo, Spain

    Luis M. Quirós

  3. Department of Pathology, Hospital Universitario Central de Asturias, Oviedo, Spain

    Jorge Santos-Juanes

  4. Deparment of Cellular Pathology, University College Hospital London, London, UK

    María Pane-Foix & Teresa Marafioti

  5. Service of Anatomic Pathology, Hospital Universitario de Araba-Txagorritxu, C/Jose Atxotegui s/n, 01009, Vitoria-Gasteiz, Alava, Spain

    Iván Fernández-Vega

Authors
  1. Iván Fernández-Vega
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luis M. Quirós
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jorge Santos-Juanes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. María Pane-Foix
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Teresa Marafioti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Iván Fernández-Vega.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fernández-Vega, I., Quirós, L.M., Santos-Juanes, J. et al. Bruton’s tyrosine kinase (Btk) is a useful marker for Hodgkin and B cell non-Hodgkin lymphoma. Virchows Arch 466, 229–235 (2015). https://doi.org/10.1007/s00428-014-1698-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-014-1698-z

Keywords

Search

Navigation