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Antiapoptotic effect of interleukin-2 (IL-2) in B-CLL cells with low and high affinity IL-2 receptors

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Abstract

Although B chronic lymphocytic leukemia (B-CLL) cells express the alpha chain of the interleukin-2 (IL-2) receptor CD25, little is known about the effect of IL-2 on apoptosis in B-CLL cells. We have shown previously that stimulation of B-CLL cells with a CpG-oligonucleotide induces IL-2 high affinity receptors. In our current work, we analyzed the effect of IL-2 on apoptosis in resting B-CLL cells and in our model of activated B-CLL cells (CD25 high cells). IL-2 had modest antiapoptotic activity in resting B-CLL cells. In contrast, IL-2 was much more potent to prevent apoptosis in activated cells. Prevention of cell death was also associated with the maintenance of the mitochondrial membrane potential. While only limited regulation of apoptosis controlling proteins was observed in resting B-CLL cells, IL-2 had strong effects on MCL-1, Bcl-xl, and survivin expression and inhibited Bax cleavage in CD25 high cells. Interestingly, expression of Bcl-2 was reduced. Addition of IL-2 to activated B-CLL cells caused rapid phosphorylation of Akt, while IL-2 failed to significantly phosphorylate Akt in resting B-CLL cells. Pharmacological inhibition of Akt by LY294002 restored sensitivity of activated B-CLL cells to fludarabine. IL-2 might be an important survival factor in activated B-CLL cells and might contribute to disease progression by upregulation of several critical antiapoptotic proteins.

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References

  1. O'Brien S, del Giglio A, Keating M (1995) Advances in the biology and treatment of B-cell chronic lymphocytic leukemia. Blood 85:307–318

    PubMed  Google Scholar 

  2. Chiorazzi N (2007) Cell proliferation and death: forgotten features of chronic lymphocytic leukemia B cells. Best Pract Res Clin Haematol 20:399–413

    Article  CAS  PubMed  Google Scholar 

  3. Messmer BT, Messmer D, Allen SL, Kolitz JE, Kudalkar P, Cesar D, Murphy EJ, Koduru P, Ferrarini M, Zupo S, Cutrona G, Damle RN, Wasil T, Rai KR, Hellerstein MK, Chiorazzi N (2005) In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest 115:755–764

    CAS  PubMed  Google Scholar 

  4. Ghia P, Circosta P, Scielzo C, Vallario A, Camporeale A, Granziero L, Caligaris-Cappio F (2005) Differential effects on CLL cell survival exerted by different microenvironmental elements. Curr Top Microbiol Immunol 294:135–145

    Article  CAS  PubMed  Google Scholar 

  5. Caligaris-Cappio F, Hamblin TJ (1999) B-cell chronic lymphocytic leukemia: a bird of a different feather. J Clin Oncol 17:399–408

    CAS  PubMed  Google Scholar 

  6. Patten PE, Buggins AG, Richards J, Wotherspoon A, Salisbury J, Mufti GJ, Hamblin TJ, Devereux S (2008) CD38 expression in chronic lymphocytic leukemia is regulated by the tumor microenvironment. Blood 111:5173–5181

    Article  CAS  PubMed  Google Scholar 

  7. Giri JG, Ahdieh M, Eisenman J, Shanebeck K, Grabstein K, Kumaki S, Namen A, Park LS, Cosman D, Anderson D (1994) Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J 13:2822–2830

    CAS  PubMed  Google Scholar 

  8. Malek TR (2008) The biology of interleukin-2. Annu Rev Immunol 26:453–479

    Article  CAS  PubMed  Google Scholar 

  9. Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, Johnston J, Madden K, Xu W, West J, Schrader S, Burkhead S, Heipel M, Brandt C, Kuijper JL, Kramer J, Conklin D, Presnell SR, Berry J, Shiota F, Bort S, Hambly K, Mudri S, Clegg C, Moore M, Grant FJ, Lofton-Day C, Gilbert T, Rayond F, Ching A, Yao L, Smith D, Webster P, Whitmore T, Maurer M, Kaushansky K, Holly RD, Foster D (2000) Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408:57–63

    Article  CAS  PubMed  Google Scholar 

  10. Nelson BH, Willerford DM (1998) Biology of the interleukin-2 receptor. Adv Immunol 70:1–81

    Article  CAS  PubMed  Google Scholar 

  11. Lin JX, Leonard WJ (2000) The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene 19:2566–2576

    Article  CAS  PubMed  Google Scholar 

  12. Damle RN, Ghiotto F, Valetto A, Albesiano E, Fais F, Yan XJ, Sison CP, Allen SL, Kolitz J, Schulman P, Vinciguerra VP, Budde P, Frey J, Rai KR, Ferrarini M, Chiorazzi N (2002) B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes. Blood 99:4087–4093

    Article  CAS  PubMed  Google Scholar 

  13. Decker T, Schneller F, Kronschnabl M, Dechow T, Lipford GB, Wagner H, Peschel C (2000) Immunostimulatory CpG-oligonucleotides induce functional high affinity IL-2 receptors on B-CLL cells: costimulation with IL-2 results in a highly immunogenic phenotype. Exp Hematol 28:558–568

    Article  CAS  PubMed  Google Scholar 

  14. Fluckiger AC, Garrone P, Durand I, Galizzi JP, Banchereau J (1993) Interleukin 10 (IL-10) upregulates functional high affinity IL-2 receptors on normal and leukemic B lymphocytes. J Exp Med 178:1473–1481

    Article  CAS  PubMed  Google Scholar 

  15. Tomic J, White D, Shi Y, Mena J, Hammond C, He L, Miller RL, Spaner DE (2006) Sensitization of IL-2 signaling through TLR-7 enhances B lymphoma cell immunogenicity. J Immunol 176:3830–3839

    CAS  PubMed  Google Scholar 

  16. Decker T, Schneller F, Hipp S, Miething C, Jahn T, Duyster J, Peschel C (2002) Cell cycle progression of chronic lymphocytic leukemia cells is controlled by cyclin D2, cyclin D3, cyclin-dependent kinase (cdk) 4 and the cdk inhibitor p27. Leukemia 16:327–334

    Article  CAS  PubMed  Google Scholar 

  17. Tretter T, Schuler M, Schneller F, Brass U, Esswein M, Aman MJ, Huber C, Peschel C (1998) Direct cellular interaction with activated CD4(+) T cells overcomes hyporesponsiveness of B-cell chronic lymphocytic leukemia in vitro. Cell Immunol 189:41–50

    Article  CAS  PubMed  Google Scholar 

  18. Mellstedt H, Choudhury A (2006) T and B cells in B-chronic lymphocytic leukaemia: faust, mephistopheles and the pact with the devil. Cancer Immunol Immunother 55:210–220

    Article  CAS  PubMed  Google Scholar 

  19. Jahrsdorfer B, Jox R, Muhlenhoff L, Tschoep K, Krug A, Rothenfusser S, Meinhardt G, Emmerich B, Endres S, Hartmann G (2002) Modulation of malignant B cell activation and apoptosis by bcl-2 antisense ODN and immunostimulatory CpG ODN. J Leukoc Biol 72:83–92

    CAS  PubMed  Google Scholar 

  20. Jahrsdorfer B, Muhlenhoff L, Blackwell SE, Wagner M, Poeck H, Hartmann E, Jox R, Giese T, Emmerich B, Endres S, Weiner GJ, Hartmann G (2005) B-cell lymphomas differ in their responsiveness to CpG oligodeoxynucleotides. Clin Cancer Res 11:1490–1499

    Article  CAS  PubMed  Google Scholar 

  21. Longo PG, Laurenti L, Gobessi S, Petlickovski A, Pelosi M, Chiusolo P, Sica S, Leone G, Efremov DG (2007) The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease. Leukemia 21:110–120

    Article  CAS  PubMed  Google Scholar 

  22. Jones DT, Ganeshaguru K, Anderson RJ, Jackson TR, Bruckdorfer KR, Low SY, Palmqvist L, Prentice HG, Hoffbrand AV, Mehta AB, Wickremasinghe RG (2003) Albumin activates the AKT signaling pathway and protects B-chronic lymphocytic leukemia cells from chlorambucil- and radiation-induced apoptosis. Blood 101:3174–3180

    Article  CAS  PubMed  Google Scholar 

  23. Lockyer HM, Tran E, Nelson BH (2007) STAT5 is essential for Akt/p70S6 kinase activity during IL-2-induced lymphocyte proliferation. J Immunol 179:5301–5308

    CAS  PubMed  Google Scholar 

  24. Bayascas JR, Alessi DR (2005) Regulation of Akt/PKB Ser473 phosphorylation. Mol Cell 18:143–145

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. Nelson BH (2004) IL-2, regulatory T cells, and tolerance. J Immunol 172:3983–3988

    CAS  PubMed  Google Scholar 

  27. Karray S, DeFrance T, Merle-Beral H, Banchereau J, Debre P, Galanaud P (1988) Interleukin 4 counteracts the interleukin 2-induced proliferation of monoclonal B cells. J Exp Med 168:85–94

    Article  CAS  PubMed  Google Scholar 

  28. Rezvany MR, Jeddi-Tehrani M, Wigzell H, Osterborg A, Mellstedt H (2003) Leukemia-associated monoclonal and oligoclonal TCR-BV use in patients with B-cell chronic lymphocytic leukemia. Blood 101:1063–1070

    Article  CAS  PubMed  Google Scholar 

  29. Beyer M, Kochanek M, Darabi K, Popov A, Jensen M, Endl E, Knolle PA, Thomas RK, von Bergwelt-Baildon M, Debey S, Hallek M, Schultze JL (2005) Reduced frequencies and suppressive function of CD4 + CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 106:2018–2025

    Article  CAS  PubMed  Google Scholar 

  30. Granziero L, Ghia P, Circosta P, Gottardi D, Strola G, Geuna M, Montagna L, Piccoli P, Chilosi M, Caligaris-Cappio F (2001) Survivin is expressed on CD40 stimulation and interfaces proliferation and apoptosis in B-cell chronic lymphocytic leukemia. Blood 97:2777–2783

    Article  CAS  PubMed  Google Scholar 

  31. Ghia P, Strola G, Granziero L, Geuna M, Guida G, Sallusto F, Ruffing N, Montagna L, Piccoli P, Chilosi M, Caligaris-Cappio F (2002) Chronic lymphocytic leukemia B cells are endowed with the capacity to attract CD4+, CD40L + T cells by producing CCL22. Eur J Immunol 32:1403–1413

    Article  CAS  PubMed  Google Scholar 

  32. Decker T, Flohr T, Trautmann P, Aman MJ, Holter W, Majdic O, Huber C, Peschel C (1995) Role of accessory cells in cytokine production by T cells in chronic B-cell lymphocytic leukemia. Blood 86:1115–1123

    CAS  PubMed  Google Scholar 

  33. Caligaris-Cappio F, Ghia P (2008) Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease? J Clin Oncol 26:4497–4503

    Article  CAS  PubMed  Google Scholar 

  34. Pepper C, Lin TT, Pratt G, Hewamana S, Brennan P, Hiller L, Hills R, Ward R, Starczynski J, Austen B, Hooper L, Stankovic T, Fegan C (2008) Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers. Blood 112:3807–3817

    Article  CAS  PubMed  Google Scholar 

  35. Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A 102:13944–13949

    Article  CAS  PubMed  Google Scholar 

  36. Willimott S, Baou M, Naresh K, Wagner SD (2007) CD154 induces a switch in pro-survival Bcl-2 family members in chronic lymphocytic leukaemia. Br J Haematol 138:721–732

    Article  CAS  PubMed  Google Scholar 

  37. Zinkel S, Gross A, Yang E (2006) BCL2 family in DNA damage and cell cycle control. Cell Death Differ 13:1351–1359

    Article  CAS  PubMed  Google Scholar 

  38. Smit LA, Hallaert DY, Spijker R, de Goeij B, Jaspers A, Kater AP, van Oers MH, van Noesel CJ, Eldering E (2007) Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity. Blood 109:1660–1668

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  40. Deaglio S, Malavasi F (2009) Chronic lymphocytic leukemia microenvironment: shifting the balance from apoptosis to proliferation. Haematologica 94:752–756

    Article  CAS  PubMed  Google Scholar 

  41. Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550–562

    Article  CAS  PubMed  Google Scholar 

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Authorship

Thomas Decker designed the study, performed experiments, and wrote the paper.

Christian Bogner performed experiments.

Madlen Oelsner performed experiments.

Christian Peschel was involved in the design of the study.

Ingo Ringshausen supervised experiments and was involved in the design of the study.

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Authors and Affiliations

  1. Third Department of Medicine, Technical University of Munich, Munich, Germany

    Thomas Decker, Christian Bogner, Madlen Oelsner, Christian Peschel & Ingo Ringshausen

  2. Onkologie Ravensburg, Wilhelm Hauff Str 41, 88214, Ravensburg, Germany

    Thomas Decker

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  1. Thomas Decker
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  2. Christian Bogner
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  3. Madlen Oelsner
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  4. Christian Peschel
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  5. Ingo Ringshausen
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Corresponding author

Correspondence to Thomas Decker.

Additional information

This work was supported by a research grant from the Jose Carreras Leukemia fund R05/17.

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Decker, T., Bogner, C., Oelsner, M. et al. Antiapoptotic effect of interleukin-2 (IL-2) in B-CLL cells with low and high affinity IL-2 receptors. Ann Hematol 89, 1125–1132 (2010). https://doi.org/10.1007/s00277-010-0994-1

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  • DOI: https://doi.org/10.1007/s00277-010-0994-1

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