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Myelodysplagias

Cytolytic function and survival of natural killer cells are severely altered in myelodysplastic syndromes

Leukemia volume 20, pages 463–470 (2006)Cite this article

Abstract

Natural Killer (NK) cells are critical in host defense against malignant transformation and are potent antileukemic cytotoxic effectors. In the present study, we investigated the peripheral NK function in patients with myelodysplastic syndromes (MDS). We demonstrated that the peripheral NK cell population was quantitatively normal in MDS patients. Furthermore, NK cells displayed an expression of the activating natural cytotoxicity receptors (NCR) NKp46 and NKp30 as well as NKG2D similar to that observed in donors, but exert a highly decreased constitutive cytolytic activity compared to resting normal NK cells. Although activation with IL-2 resulted in the upregulation of NKp46 expression by MDS-NK cells, their cytolytic function remained deeply altered as compared to activated donor NK cells. In addition, MDS NK cells did not proliferate in vitro, and displayed an increased rate of apoptosis in response to IL-2 stimulation although the spontaneous apoptosis was not significantly increased. Interestingly, a proportion of peripheral MDS-NK cells were derived from the MDS clone as the cytogenetic anomaly found in bone marrow karyotype was also detected in 20–50% of circulating NK cells. In conclusion, NK cells' cytolytic function and proliferative capacities in response to activation by cytokines are profoundly altered in MDS.

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References

  1. Heaney M, Golde D . Myelodysplasia. N Engl J Med 1999; 340: 1649–1660.

    Article  CAS  PubMed  Google Scholar 

  2. Bennett J, Catovsky D, Daniel M, Flandrin G, Galton D, Gralnick H et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51: 189–199.

    Article  CAS  PubMed  Google Scholar 

  3. Brunning R, Bennett J, Flandrin G . Myelodysplstics syndromes. In: ES Jaffe, NL Harris, H Stein and JW Vardiman (eds.) WHO Classification of Tumours: Pathology and Genetics of Haematopoietic and lymphoid tissues. Lyon: IARC Press, 2001, P 61–73.

    Google Scholar 

  4. Greenberg P . The Myelodysplastics Syndromes, 3rd (ed.) Churchill Livingstone: New York, 2000.

    Google Scholar 

  5. Cheson B, Bennett J, Kantarjian H, Pinto A, Schiffer C, Nimer S, group WHOWiw. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 2000; 96: 3671–3674.

    CAS  PubMed  Google Scholar 

  6. Hamblin T . Immunology of the myelodysplastic syndromes. In: Bennet JM (ed.) The Myelodysplastic Syndromes Syndromes: Pathobiology and Clinical Management. Marcel Dekker: New York, 2002, P 65–67.

    Google Scholar 

  7. Greenberg P, Young N, Gatterman N . Myelodysplastic syndromes. Hematology 2002; 1: 136–161.

    Article  Google Scholar 

  8. Molldrem J, Leifer E, Bahceci E, Saunthararajah Y, Rivera M, Dunbar C et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med 2002; 137: 156–163.

    Article  PubMed  Google Scholar 

  9. Sorskaar D, Forre O, Albrechtsen D, Stavem P . Decreased natural killer cell activity versus normal natural killer cell markers in mononuclear cells from patients with smouldering leukemia. Scand J Haematol 1986; 37: 154–161.

    Article  CAS  PubMed  Google Scholar 

  10. Ogata K, Fujii H, Yokose N, An E, Tamura H, Kamikubo K et al. Defective natural killer (NK) cell-mediated cytotoxicity does not imply clonal involvement of NK cells in myelodysplastic syndromes. Br J Haematol 1994; 87: 396–398.

    Article  CAS  PubMed  Google Scholar 

  11. Farag S, Fehniger T, Ruggeri L, Velardi A, Caligiuri M . Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect. Blood 2002; 100: 1935–1947.

    Article  CAS  PubMed  Google Scholar 

  12. Uhrberg M, Valiante N, Shum BP, Shilling H, Lienert-Weidenbach K, Corliss B et al. Human diversity in killer cell inhibitory receptor genes. Immunity 1997; 7: 753–763.

    Article  CAS  PubMed  Google Scholar 

  13. Long E . Regulation of immune responses through inhibitory receptors. Annu Rev Immunol 1999; 17: 875–904.

    Article  CAS  PubMed  Google Scholar 

  14. Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari M et al. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 2001; 19: 197–223.

    Article  CAS  PubMed  Google Scholar 

  15. Sivori S, Vitale M, Morelli L, Sanseverino L, Augugliaro R, Bottino C et al. p46, a novel natural killer cell-specific surface molecule that mediates cell activation. J Exp Med 1997; 186: 1129–1136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pende D, Parolini S, Pessino A, Sivori S, Augugliaro R, Morelli L et al. Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J Exp Med 1999; 190: 1505–1516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sivori S, Pende D, Bottino C, Marcenaro E, Pessino A, Biassoni R et al. NKp46 is the major triggering receptor involved in the natural cytotoxicity of fresh or cultured human NK cells. Correlation between surface density of NKp46 and natural cytotoxicity against autologous, allogeneic or xenogeneic target cells. Eur J Immunol 1999; 29: 1656–1666.

    Article  CAS  PubMed  Google Scholar 

  18. Bauer S, Groh V, Wu J, Steinle A, Phillips J, Lanier L et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999; 285: 727–729.

    Article  CAS  PubMed  Google Scholar 

  19. Cerwenka A, Lanier L . Natural killer cells, viruses and cancer. Nat Rev Immunol 2001; 1: 41–49.

    Article  CAS  PubMed  Google Scholar 

  20. Wu J, Lanier L . Natural killer cells and cancer. Adv Cancer Res 2003; 90: 127–156.

    Article  CAS  PubMed  Google Scholar 

  21. Tajima F, Kawatani T, Endo A, Kawasaki H . Natural killer cell activity and cytokine production as prognostic factors in adult acute leukemia. Leukemia 1996; 10: 478–482.

    CAS  PubMed  Google Scholar 

  22. Greenberg P, Cox C, LeBeau M, Fenaux P, Morel P, Sanz G et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088.

    CAS  PubMed  Google Scholar 

  23. Carayol G, Robin C, Bourhis J, Bennaceur-Griscelli A, Chouaib S, Coulombel L et al. NK cells differentiated from bone marrow, cord blood and peripheral blood stem cells exhibit similar phenotype and functions. Eur J Immunol 1998; 28: 1991–2000.

    Article  CAS  PubMed  Google Scholar 

  24. Pross H, Baines M, Rubin P, Shragge P, Patterson M . Spontaneous human lymphocyte-mediated cytotoxicity against tumor target cells. IX. The quantitation of natural killer cell activity. J Clin Immunol 1981; 1: 51–63.

    Article  CAS  PubMed  Google Scholar 

  25. Castedo M, Ferri K, Roumier T, Metivier D, Zamzami N, Kroemer G . Quantitation of mitochondrial alterations associated with apoptosis. J Immunol Meth 2002; 265: 39–47.

    Article  CAS  Google Scholar 

  26. Costello R, Sivori S, Marcenaro E, Lafage-Pochitaloff M, Mozziconacci M, Reviron D et al. Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia. Blood 2002; 99: 3661–3667.

    Article  CAS  PubMed  Google Scholar 

  27. Ogata K, Yokose N, Ito T, An E, Tamura H, Dan K et al. Assessment of therapeutic potential of interleukin 2 for myelodysplastic syndromes. Br J Haematol 1994; 86: 562–567.

    Article  CAS  PubMed  Google Scholar 

  28. Cortelezzi A, Sarina B, Cattaneo C, Pomati M, Silvestris I, Soligo D et al. In vitro effects of IL-2 on NK-activity, clonogenic potential, blast cell proliferation and cytokine release of MDS bone marrow patients. Leukemia 1996; 10: 1181–1189.

    CAS  PubMed  Google Scholar 

  29. Salih H, Antropius H, Gieseke F, Lutz S, Kanz L, Rammensee H et al. Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood 2003; 102: 1389–1396.

    Article  CAS  PubMed  Google Scholar 

  30. Baniyash M . TCR zeta-chain downregulation: curtailing an excessive inflammatory immune response. Nat Rev Immunol 2004; 4 (9): 675–687.

    Article  CAS  PubMed  Google Scholar 

  31. Arnon T, Achdout H, Levi O, Markel G, Saleh N, Katz G et al. Inhibition of the NKp30activating receptor by pp65 of human cytomegalovirus. Nat Immunol 2005; 6: 515–523.

    Article  CAS  PubMed  Google Scholar 

  32. Chen X, Woiciechowsky A, Raffegerst S, Schendel D, Kolb H, Roskrow M . Impaired expression of the CD3-zeta chain in peripheral blood T cells of patients with chronic myeloid leukaemia results in an increased susceptibility to apoptosis. Br J Haematol 2000; 111: 815–825.

    Google Scholar 

  33. Guven H, Gilljam M, Chambers B, Ljunggren H, Christensson B, Kimby E et al. Expansion of natural killer (NK) and natural killer-like T (NKT)-cell populations derived from patients with B-chronic lymphocytic leukemia (B-CLL): a potential source for cellular immunotherapy. Leukemia 2003; 17: 1973–1980.

    Article  CAS  PubMed  Google Scholar 

  34. Verhoef G, Schouwer PD, Ceuppens J, Damme JV, Goossens W, Boogaerts M . Measurement of serum cytokine levels in patients with myelodysplastic syndromes. Leukemia 1992; 6: 1268–1272.

    CAS  PubMed  Google Scholar 

  35. Poggi A, Massaro AM, Negrini S, Contini P, Zocchi MR . Tumor-induced apoptosis of human IL-2-activated NK cells: role of natural cytotoxicity receptors. J Immunol 2005; 174 (5): 2653–2660.

    Article  CAS  PubMed  Google Scholar 

  36. Raskind W, Steinmann L, Najfeld V . Clonal development of myeloproliferative disorders: clues to hematopoietic differentiation and multistep pathogenesis of cancer. Leukemia 1998; 12: 108–116.

    Article  CAS  PubMed  Google Scholar 

  37. Nilsson L, Astrand-Grundstrom I, Arvidsson I, Jacobsson B, Hellstrom-Lindberg E, Hast R et al. Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level. Blood 2000; 96: 2012–2021.

    CAS  PubMed  Google Scholar 

  38. Nakazawa T, Koike K, Agematsu K, Itoh S, Hagimoto R, Kitazawa Y et al. Cytogenetic clonality analysis in monosomy 7 associated with juvenile myelomonocytic leukemia: clonality in B and NK cells, but not in T cells. Leuk Res 1998; 22: 887–892.

    Article  CAS  PubMed  Google Scholar 

  39. Miura I, Kobayashi Y, Takahashi N, Saitoh K, Miura A . Involvement of natural killer cells in patients with myelodysplastic syndrome carrying monosomy 7 revealed by the application of fluorescence in situ hybridization to cells collected by means of fluorescence-activated cell sorting. Br J Haematol 2000; 110: 876–879.

    Article  CAS  PubMed  Google Scholar 

  40. Nand S, Stock W, Stiff P, Sosman J, Martone B, Radvany R . A phase II trial of interleukin-2 in myelodysplastic syndromes. Br J Haematol 1998; 101: 205–207.

    Article  CAS  PubMed  Google Scholar 

  41. Ogata K, Yokose N, Nomura T . Interleukin-2 therapy for myelodysplastic syndrome: does it work? Leuk Lymphoma 1995; 17: 411–415.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by Grants from INSERM and La Fondation de France (comité Leucémie). We thank Abdelali Jalil for confocal microscopy analyses and Yann Lecluse and Didier Métivier for flow cytometry analyses.

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Authors and Affiliations

  1. INSERM U487, Institut Gustave Roussy, Villejuif, France

    J-J Kiladjian, E Bourgeois, I Lobe, G Visentin, J-H Bourhis, S Chouaib & A Caignard

  2. Service d'Hematologie Clinique, Hôpital Avicenne, Paris 13 University, Villejuif, France

    J-J Kiladjian, I Lobe & P Fenaux

  3. UMR8125, Institut Gustave Roussy, Villejuif, France

    T Braun

  4. Service d'Hematologie, Institut Gustave Roussy,

    J-H Bourhis

  5. 39 rue Camille Desmoulins, Villejuif, France

    J-H Bourhis

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  1. J-J Kiladjian
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Correspondence to A Caignard.

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Kiladjian, JJ., Bourgeois, E., Lobe, I. et al. Cytolytic function and survival of natural killer cells are severely altered in myelodysplastic syndromes. Leukemia 20, 463–470 (2006). https://doi.org/10.1038/sj.leu.2404080

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  • DOI: https://doi.org/10.1038/sj.leu.2404080

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