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ALL

Immunosurveillance of childhood ALL: polymorphic interferon-γ alleles are associated with age at diagnosis and clinical risk groups

Leukemia volume 19, pages 44–48 (2005)Cite this article

Abstract

Interferon-γ (IFN-γ) has been implicated as an important mediator of antitumor immunity in murine model systems. To determine whether a CA-repeat associated with differential NFκB-binding and IFN-γ-expression levels may influence the incidence, manifestation and early clinical treatment response of childhood acute lymphoblastic leukemia, we performed PCR-based genotyping of 393 patients with ALL and 207 healthy controls. We could not find any differences in the allele distribution comparing patients and controls. However, when we further analyzed the allele frequencies with respect to age of clinical manifestation, we found that patients with B-lineage ALL showing the IFN-γ high-expressing genotype presented at a more advanced age compared to those patients with intermediate and low-expressing genotypes (median 6 vs 4.4 years, P=0.01). Furthermore, we found a significantly higher number of low expressors in the group of high-risk patients (HR n=32 and MR/SR n=266, P=0.025, defined by prednisone response, cytological remission and minimal residual disease (MRD)) with B-lineage ALL. Thus, we provide evidence that polymorphic IFN-γ alleles are associated with age at clinical presentation and risk groups such as prednisone response in B-lineage ALL, suggesting distinct effects of IFN-γ in immunosurveillance and early response to steroid therapy.

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References

  1. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD . Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3: 991–998.

    Article  CAS  Google Scholar 

  2. Street SE, Cretney E, Smyth MJ . Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. Blood 2001; 97: 192–197.

    Article  CAS  Google Scholar 

  3. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001; 410: 1107–1111.

    Article  CAS  Google Scholar 

  4. Dighe AS, Richards E, Old LJ, Schreiber RD . Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors. Immunity 1994; 1: 447–456.

    Article  CAS  Google Scholar 

  5. Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA 1998; 95: 7556–7561.

    Article  CAS  Google Scholar 

  6. Pravica V, Asderakis A, Perrey C, Hajeer A, Sinnott PJ, Hutchinson IV . In vitro production of IFN-gamma correlates with CA repeat polymorphism in the human IFN-gamma gene. Eur J Immunogenet 1999; 26: 1–3.

    Article  CAS  Google Scholar 

  7. Pravica V, Perrey C, Stevens A, Lee JH, Hutchinson IV . A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. Hum Immunol 2000; 61: 863–866.

    Article  CAS  Google Scholar 

  8. Siegmund T, Usadel KH, Donner H, Braun J, Walfish PG, Badenhoop K . Interferon-gamma gene microsatellite polymorphisms in patients with Graves' disease. Thyroid 1998; 8: 1013–1017.

    Article  CAS  Google Scholar 

  9. Jahromi M, Millward A, Demaine A . A CA repeat polymorphism of the IFN-gamma gene is associated with susceptibility to type 1 diabetes. J Interferon Cytokine Res 2000; 20: 187–190.

    Article  CAS  Google Scholar 

  10. Jahromi MM, Millward BA, Demaine AG . A polymorphism in the promoter region of the gene for interleukin-6 is associated with susceptibility to type 1 diabetes mellitus. J Interferon Cytokine Res 2000; 20: 885–888.

    Article  CAS  Google Scholar 

  11. Pokorny V, McLean L, McQueen F, Abu-Maree M, Yeoman S . Interferon-gamma microsatellite and rheumatoid arthritis. Lancet 2001; 358: 122–123.

    Article  CAS  Google Scholar 

  12. Lee JY, Goldman D, Piliero LM, Petri M, Sullivan KE . Interferon-gamma polymorphisms in systemic lupus erythematosus. Genes Immun 2001; 2: 254–257.

    Article  CAS  Google Scholar 

  13. Asderakis A, Sankaran D, Dyer P, Johnson RW, Pravica V, Sinnott PJ et al. Association of polymorphisms in the human interferon-gamma and interleukin-10 gene with acute and chronic kidney transplant outcome: the cytokine effect on transplantation. Transplantation 2001; 71: 674–677.

    Article  CAS  Google Scholar 

  14. Cavet J, Dickinson AM, Norden J, Taylor PR, Jackson GH, Middleton PG . Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation. Blood 2001; 98: 1594–1600.

    Article  CAS  Google Scholar 

  15. Awad M, Pravica V, Perrey C, El Gamel A, Yonan N, Sinnott PJ et al. CA repeat allele polymorphism in the first intron of the human interferon-gamma gene is associated with lung allograft fibrosis. Hum Immunol 1999; 60: 343–346.

    Article  CAS  Google Scholar 

  16. Rossouw M, Nel HJ, Cooke GS, van Helden PD, Hoal EG . Association between tuberculosis and a polymorphic NFkappaB binding site in the interferon gamma gene. Lancet 2003; 361: 1871–1872.

    Article  CAS  Google Scholar 

  17. Reynard MP, Turner D, Junqueira-Kipnis AP, Ramos de Souza M, Moreno C, Navarrete CV . Allele frequencies for an interferon-gamma microsatellite in a population of Brazilian leprosy patients. Eur J Immunogenet 2003; 30: 149–151.

    Article  CAS  Google Scholar 

  18. Mekus F, Dork T, Deufel T, Morral N, Tummler B . Analysis of microsatellites by direct blotting electrophoresis and chemiluminescence detection. Electrophoresis 1995; 16: 1886–1888.

    Article  CAS  Google Scholar 

  19. Nieters A, Brems S, Becker N . Cross-sectional study on cytokine polymorphisms, cytokine production after T-cell stimulation and clinical parameters in a random sample of a German population. Hum Genet 2001; 108: 241–248.

    Article  CAS  Google Scholar 

  20. Greaves MF, Wiemels J . Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 2003; 3: 639–649.

    Article  CAS  Google Scholar 

  21. Salkowski CA, Vogel SN . IFN-gamma mediates increased glucocorticoid receptor expression in murine macrophages. J Immunol 1992; 148: 2770–2777.

    CAS  PubMed  Google Scholar 

  22. Schmiegelow K, Garred P, Lausen B, Andreassen B, Petersen BL, Madsen HO . Increased frequency of mannose-binding lectin insufficiency among children with acute lymphoblastic leukemia. Blood 2002; 100: 3757–3760.

    Article  CAS  Google Scholar 

  23. Lauten M, Matthias T, Stanulla M, Beger C, Welte K, Schrappe M . Association of initial response to prednisone treatment in childhood acute lymphoblastic leukaemia and polymorphisms within the tumour necrosis factor and the interleukin-10 genes. Leukemia 2002; 16: 1437–1442.

    Article  CAS  Google Scholar 

  24. Dabora SL, Roberts P, Nieto A, Perez R, Jozwiak S, Franz D et al. Association between a high-expressing interferon-gamma allele and a lower frequency of kidney angiomyolipomas in TSC2 patients. Am J Hum Genet 2002; 71: 750–758.

    Article  Google Scholar 

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Acknowledgements

We are grateful to all patients, families, healthy volunteers and medical personnel supporting this study. We thank Professor Hartmut Hecker for expert statistical advice and Dr Frauke Mekus for expert technical advice. This work has been supported by the Parents Foundation and the Hoselmann Foundation, Hannover.

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Authors and Affiliations

  1. Department of Pediatric Hematology/Oncology, Medical School Hannover, Children's Hospital, Hannover, Germany

    T Cloppenborg, M Stanulla, M Zimmermann, M Schrappe, K Welte & C Klein

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  1. T Cloppenborg
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  2. M Stanulla
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  3. M Zimmermann
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  4. M Schrappe
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  5. K Welte
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Correspondence to C Klein.

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Cloppenborg, T., Stanulla, M., Zimmermann, M. et al. Immunosurveillance of childhood ALL: polymorphic interferon-γ alleles are associated with age at diagnosis and clinical risk groups. Leukemia 19, 44–48 (2005). https://doi.org/10.1038/sj.leu.2403553

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