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 Article
  • Published:

Chronic Lymphocytic Leukemia

Lyn-mediated SHP-1 recruitment to CD5 contributes to resistance to apoptosis of B-cell chronic lymphocytic leukemia cells

Leukemia volume 25, pages 1768–1781 (2011)Cite this article

Subjects

Abstract

In B-cell chronic lymphocytic leukemia (B-CLL) cells, Lyn, a tyrosine kinase belonging to the Src family, is overexpressed and atypically localized in an aberrant cytosolic complex in an active conformation, contributing to the unbalance between cell survival and pro-apoptotic signals. In this study, we demonstrate that Lyn constitutively phosphorylates the immunoreceptor tyrosine inhibitory motifs of the inhibitory cell surface co-receptor CD5, a marker of B-CLL. As a result, CD5 provides an anchoring site to Src homology 2 domain-containing phosphatase 1 (SHP-1), a known negative regulator of hematopoietic cell function, thereby triggering the negative B-cell receptor (BCR) signaling. The subsequent segregation of SHP-1 into two pools, one bound to the inhibitory co-receptor CD5 in an active form, the other in the cytosol in an inhibited conformation, proves crucial for withstanding apoptosis, as shown by the use of phosphotyrosine phosphatase-I-I, a direct inhibitor of SHP-1, or SHP-1 knockdown. These results confirm that Lyn exhibits the unique ability to negatively regulate BCR signaling, in addition to positively regulating effectors downstream of the BCR, and identify SHP-1 as a novel player in the deranged signaling network and as a potential attractive target for new therapeutic strategies 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
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Stevenson FK, Caligaris-Cappio F . Chronic lymphocytic leukemia: revelations from the B-cell receptor. Blood 2004; 103: 4389–4395.

    Article  CAS  PubMed  Google Scholar 

  2. Chiorazzi N, Rai KR, Ferrarini M . Chronic lymphocytic leukemia. N Engl J Med 2005; 352: 804–815.

    Article  CAS  PubMed  Google Scholar 

  3. Cuni S, Perez-Aciego P, Perez-Chacon G, Vargas JA, Sanchez A, Martin-Saavedra FM et al. A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells. Leukemia 2004; 18: 1391–1400.

    Article  CAS  PubMed  Google Scholar 

  4. Longo PG, Laurenti L, Gobessi S, Sica S, Leone G, Efremov DG . The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells. Blood 2008; 111: 846–855.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. 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 

  7. Kraus M, Pao LI, Reichlin A, Hu Y, Canono B, Cambier JC et al. Interference with immunoglobulin (Ig)α immunoreceptor tyrosine-based activation motif (ITAM) phosphorylation modulates or blocks B cell development, depending on the availability of an Igβ cytoplasmic tail. J Exp Med 2001; 194: 455–469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kurosaki T . Regulation of B cell fates by BCR signaling components. Curr Opin Immunol 2002; 14: 341–347.

    Article  CAS  PubMed  Google Scholar 

  9. Niiro H, Clark EA . Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol 2002; 2: 945–956.

    Article  CAS  PubMed  Google Scholar 

  10. Cambier JC . Antigen and Fc receptor signaling. The awesome power of the immunoreceptor tyrosine-based activation motif (ITAM). J Immunol 1995; 155: 3281–3285.

    CAS  PubMed  Google Scholar 

  11. Rolli V, Gallwitz M, Wossning T, Flemming A, Schamel WW, Zürn C et al. Amplification of B cell antigen receptor signaling by a Syk/ITAM positive feedback loop. Mol Cell 2002; 10: 1057–1069.

    Article  CAS  PubMed  Google Scholar 

  12. Hashimoto A, Takeda K, Inaba M, Sekimata M, Kaisho T, Ikehara S et al. Cutting edge: essential role of phospholipase C-gamma 2 in B cell development and function. J Immunol 2000; 165: 1738–1742.

    Article  CAS  PubMed  Google Scholar 

  13. Gauld SB, Dal Porto JM, Cambier JC . B cell antigen receptor signaling: roles in cell development and disease. Science 2002; 296: 1641–1642.

    Article  CAS  PubMed  Google Scholar 

  14. DeFranco AL, Chan VW, Lowell CA . Positive and negative roles of the tyrosine kinase Lyn in B cell function. Semin Immunol 1998; 10: 299–307.

    Article  CAS  PubMed  Google Scholar 

  15. Xu Y, Harder KW, Huntington ND, Hibbs ML, Tarlinton DM . Lyn tyrosine kinase: accentuating the positive and the negative. Immunity 2005; 22: 9–18.

    PubMed  Google Scholar 

  16. Contri A, Brunati AM, Trentin L, Cabrelle A, Miorin M, Cesaro L et al. Chronic lymphocytic leukemia B cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis. J Clin Invest 2005; 115: 369–378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gobessi S, Laurenti L, Longo PG, Carsetti L, Berno V, Sica S et al. Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells. Leukemia 2009; 23: 686–697.

    Article  CAS  PubMed  Google Scholar 

  18. Ringshausen I, Schneller F, Bogner C, Hipp S, Duyster J, Peschel C et al. Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase C delta. Blood 2002; 100: 3741–3748.

    Article  CAS  PubMed  Google Scholar 

  19. Plate JM . PI3-kinase regulates survival of chronic lymphocytic leukemia B-cells by preventing caspase 8 activation. Leuk Lymphoma 2004; 45: 1519–1529.

    Article  CAS  PubMed  Google Scholar 

  20. Sainz-Perez A, Gary-Gouy H, Portier A, Davi F, Merle-Beral H, Galanaud P et al. High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia. Leukemia 2006; 20: 498–504.

    Article  CAS  PubMed  Google Scholar 

  21. Monroe JG . ITAM-mediated tonic signalling through pre-BCR and BCR complexes. Nat Rev Immunol 2006; 6: 283–294.

    Article  CAS  PubMed  Google Scholar 

  22. Trentin L, Frasson M, Donella-Deana A, Frezzato F, Pagano MA, Tibaldi E et al. Geldanamycin-induced Lyn dissociation from aberrant Hsp90-stabilized cytosolic complex is an early event in apoptotic mechanisms in B-chronic lymphocytic leukemia. Blood 2008; 112: 4665–4674.

    Article  CAS  PubMed  Google Scholar 

  23. Veldurthy A, Patz M, Hagist S, Pallasch CP, Wendtner CM, Hallek M et al. The kinase inhibitor dasatinib induces apoptosis in chronic lymphocytic leukemia cells in vitro with preference for a subgroup of patients with unmutated IgVH genes. Blood 2008; 112: 1443–1452.

    Article  CAS  PubMed  Google Scholar 

  24. Hallaert DY, Jaspers A, van Noesel CJ, van Oers MH, Kater AP, Eldering E . c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches. Blood 2008; 112: 5141–5149.

    Article  CAS  PubMed  Google Scholar 

  25. 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  PubMed  Google Scholar 

  26. Trentin L, Perin A, Siviero M, Piazza F, Facco M, Gurrieri C et al. B7 costimulatory molecules from malignant cells in patients with B-cell chronic lymphoproliferative disorders trigger T-cell proliferation. Cancer 2000; 89: 1259–1268.

    Article  CAS  PubMed  Google Scholar 

  27. Cerutti A, Trentin L, Zambello R, Sancetta R, Milani A, Tassinari C et al. The CD5/CD72 receptor system is coexpressed with several functionally relevant counterstructures on human B cells and delivers a critical signaling activity. J Immunol 1996; 157: 1854–1862.

    CAS  PubMed  Google Scholar 

  28. Ticchioni M, Essafi M, Jeandel PY, Davi F, Cassuto JP, Deckert M et al. Homeostatic chemokines increase survival of B-chronic lymphocytic leukemia cells through inactivation of transcription factor FOXO3a. Oncogene 2007; 26: 7081–7091.

    Article  CAS  PubMed  Google Scholar 

  29. Keilhack H, Müller M, Böhmer SA, Frank C, Weidner KM, Birchmeier W et al. Negative regulation of Ros receptor tyrosine kinase signaling. An epithelial function of the SH2 domain protein tyrosine phosphatase SHP-1. J Cell Biol 2001; 152: 325–334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bain J, McLauchlan H, Elliott M, Cohen P . The specificities of protein kinase inhibitors: an update. Biochem J 2003; 371: 199–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lorenz U . SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunol Rev 2009; 228: 342–359.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Wu C, Sun M, Liu L, Zhou GW . The function of the protein tyrosine phosphatase SHP-1 in cancer. Gene 2003; 306: 1–12.

    Article  CAS  PubMed  Google Scholar 

  33. Gabelloni ML, Borge M, Galletti J, Cañones C, Calotti PF, Bezares RF et al. SHIP-1 protein level and phosphorylation status differs between CLL cells segregated by ZAP-70 expression. Br J Haematol 2008; 140: 117–119.

    PubMed  Google Scholar 

  34. Simoncic PD, McGlade CJ, Tremblay ML . PTP1B and TC-PTP: novel roles in immune-cell signaling. Can J Physiol Pharmacol 2006; 84: 667–675.

    Article  CAS  PubMed  Google Scholar 

  35. Sen G, Bikah G, Venkataraman C, Bondada S . Negative regulation of antigen receptor-mediated signaling by constitutive association of CD5 with the SHP-1 protein tyrosine phosphatase in B-1 B cells. Eur J Immunol 1999; 29: 3319–3328.

    Article  CAS  PubMed  Google Scholar 

  36. Chumley MJ, Dal Porto JM, Cambier JC . The unique antigen receptor signaling phenotype of B-1 cells is influenced by locale but induced by antigen. J Immunol 2002; 169: 1735–1743.

    Article  CAS  PubMed  Google Scholar 

  37. Gary-Gouy H, Sainz-Perez A, Marteau JB, Marfaing-Koka A, Delic J, Merle-Beral H et al. Natural phosphorylation of CD5 in chronic lymphocytic leukemia B cells and analysis of CD5-regulated genes in a B cell line suggest a role for CD5 in malignant phenotype. J Immunol 2007; 179: 4335–4344.

    Article  CAS  PubMed  Google Scholar 

  38. Poole AW, Jones ML . A SHPing tale: perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail. Cell Signal 2005; 17: 1323–1332.

    Article  CAS  PubMed  Google Scholar 

  39. Arabaci G, Yi T, Fu H, Porter ME, Beebe KD, Pei D . alpha-bromoacetophenone derivatives as neutral protein tyrosine phosphatase inhibitors: structure-activity relationship. Bioorg Med Chem Lett 2002; 12: 3047–3050.

    Article  CAS  PubMed  Google Scholar 

  40. Baudot AD, Jeandel PY, Mouska X, Maurer U, Tartare-Deckert S, Raynaud SD et al. The tyrosine kinase Syk regulates the survival of chronic lymphocytic leukemia B cells through PKCdelta and proteasome-dependent regulation of Mcl-1 expression. Oncogene 2009; 28: 3261–3273.

    Article  CAS  PubMed  Google Scholar 

  41. López-Lago M, Lee H, Cruz C, Movilla N, Bustelo XR . Tyrosine phosphorylation mediates both activation and downmodulation of the biological activity of Vav. Mol Cell Biol 2000; 20: 1678–1691.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Thomas LW, Lam C, Edwards SW . Mcl-1; the molecular regulation of protein function. FEBS Lett 2010; 584: 2981–2989.

    Article  CAS  PubMed  Google Scholar 

  43. Akgul C . Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol Life Sci 2009; 66: 1326–1336.

    Article  CAS  PubMed  Google Scholar 

  44. Tybulewicz VL . Vav-family proteins in T-cell signalling. Curr Opin Immunol 2005; 17: 267–274.

    Article  CAS  PubMed  Google Scholar 

  45. Yokoyama WM . Inhibitory receptors signal activation. Immunity 2008; 29: 515–517.

    Article  CAS  PubMed  Google Scholar 

  46. Koncz G, Kerekes K, Chakrabandhu K, Hueber AO . Regulating Vav1 phosphorylation by the SHP-1 tyrosine phosphatase cells spend their life cycle is a fine-tuning mechanism for the negative regulation of DISC formation and Fas-mediated cell death signaling. Cell Death Differ 2008; 15: 494–503.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by AIRC (Milan) to GS, by a grant from Fondazione Berlucchi per la Ricerca sul Cancro on ‘Approccio clinico/biologico ai pazienti con leucemia linfatica cronica’ and by Regione Veneto on Chronic Lymphocytic Leucemia. AIRC Regional Project with Fondazione CARIPARO e CARIVERONA.

Author information

Author notes

  1. M A Pagano and L Trentin: These authors are co-senior authors.

Authors and Affiliations

  1. Department of Biological Chemistry, University of Padua, Padua, Italy

    E Tibaldi, A M Brunati, F Zonta & M A Pagano

  2. Department of Clinical and Experimental Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy

    F Frezzato, C Gattazzo, R Zambello, G Semenzato & L Trentin

  3. Venetian Institute for Molecular Medicine (VIMM), Centro di Eccellenza per la Ricerca Biomedica, Padua, Italy

    F Frezzato, C Gattazzo, R Zambello, G Semenzato & L Trentin

  4. Department of General Surgery and Organ Transplantation, Hepatobiliary and Liver Transplant Unit, University of Padua, Padua, Italy

    E Gringeri

Authors
  1. E Tibaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A M Brunati
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F Zonta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F Frezzato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Gattazzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R Zambello
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E Gringeri
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G Semenzato
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M A Pagano
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. L Trentin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A M Brunati.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tibaldi, E., Brunati, A., Zonta, F. et al. Lyn-mediated SHP-1 recruitment to CD5 contributes to resistance to apoptosis of B-cell chronic lymphocytic leukemia cells. Leukemia 25, 1768–1781 (2011). https://doi.org/10.1038/leu.2011.152

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.152

Keywords

This article is cited by

Search

Advanced search

Quick links