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 Manuscript
  • Published:

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 volume 16, pages 1437–1442 (2002)Cite this article

Abstract

Plasma levels of TNF and IL-10 have been associated with therapy outcome in haematological malignancies and are influenced by genetic variation due to germline polymorphisms within the TNF and IL-10 genes. Different TNF and IL-10 genetic polymorphisms might therefore also correlate with clinical outcome in childhood acute lymphoblastic leukaemia (ALL). We analysed the association of TNF and IL-10 polymorphisms with response to initial treatment and risk of relapse in 135 children with ALL, treated according to Berlin–Frankfurt–Münster (BFM) protocols. Our data showed a protective effect from prednisone poor response in patients with the IL-10 G/G genotype, whereas no association of the risk of relapse and IL-10 genotype was found. In the total study group, subjects expressing the TNF2 allele neither showed a statistically significant general association with prednisone response nor with risk of relapse compared to subjects homozygous for the TNF1 allele. Nevertheless, we did find a higher risk of relapse in poor prednisone responders expressing the TNF2 allele compared to poor prednisone responders not expressing the TNF2 allele. We conclude that IL-10 genotype might influence prednisone response in patients with childhood ALL, whereas TNF genotype seems to influence the risk of relapse in high risk ALL patients.

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

Similar content being viewed by others

References

  1. Pui CH, Evans WE . Acute lymphoblastic leukemia N Engl J Med 1998 339: 605–615

    Article  CAS  PubMed  Google Scholar 

  2. Riehm H, Feickert HJ, Schrappe M, Henze G, Schellong G . Therapy results in five ALL-BFM studies since 1970: implications of risk factors for prognosis Hamatol Bluttransfus 1987 30: 139–146

    CAS  Google Scholar 

  3. Schrappe M, Arico M, Harbott J, Biondi A, Zimmermann M, Conter V, Reiter A, Valsecchi MG, Gadner H, Basso G, Bartram CR, Lampert F, Riehm H, Masera G . Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome Blood 1998 92: 2730–2741

    CAS  PubMed  Google Scholar 

  4. Dordelmann M, Reiter A, Borkhardt A, Ludwig WD, Gotz N, Viehmann S, Gadner H, Riehm H, Schrappe M . Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia Blood 1999 94: 1209–1217

    CAS  PubMed  Google Scholar 

  5. Schrappe M, Reiter A, Zimmermann M, Harbott J, Ludwig WD, Henze G, Gadner H, Odenwald E, Riehm H . Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin–Frankfurt–Munster Leukemia 2000 14: 2205–2222

    Article  CAS  PubMed  Google Scholar 

  6. Gajjar A, Ribeiro R, Hancock ML, Rivera GK, Mahmoud H, Sandlund JT, Crist WM, Pui CH . Persistence of circulating blasts after 1 week of multiagent chemotherapy confers a poor prognosis in childhood acute lymphoblastic leukemia Blood 1995 86: 1292–1295

    CAS  PubMed  Google Scholar 

  7. Steinherz PG, Gaynon PS, Breneman JC, Cherlow JM, Grossman NJ, Kersey JH, Johnstone HS, Sather HN, Trigg ME, Chappell R, Hammond D, Bleyer WA . Cytoreduction and prognosis in acute lymphoblastic leukemia – the importance of early marrow response: report from the Childrens Cancer Group J Clin Oncol 1996 14: 389–398

    Article  CAS  PubMed  Google Scholar 

  8. Chessells JM, Bailey C, Richards SM . Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X. Medical Research Council Working Party on Childhood Leukaemia Lancet 1995 345: 143–148

    Article  CAS  PubMed  Google Scholar 

  9. Thyss A, Suciu S, Bertrand Y, Mazingue F, Robert A, Vilmer E, Mechinaud F, Benoit Y, Brock P, Ferster A, Lutz P, Boutard P, Marguerite G, Plouvier E, Michel G, Plantaz D, Munzer M, Rialland X, Chantraine JM, Norton L, Solbu G, Philippe N, Otten J . Systemic effect of intrathecal methotrexate during the initial phase of treatment of childhood acute lymphoblastic leukemia. The European Organization for Research and Treatment of Cancer Children's Leukemia Cooperative Group J Clin Oncol 1997 15: 1824–1830

    Article  CAS  PubMed  Google Scholar 

  10. Schrappe M, Reiter A, Riehm H . Cytoreduction and prognosis in childhood acute lymphoblastic leukemia J Clin Oncol 1996 14: 2403–2406

    Article  CAS  PubMed  Google Scholar 

  11. Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W, Niemeyer C, Henze G, Feldges A, Zintl F, Kornhuber B, Ritter J, Welte K, Gadner H, Riehm H . Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German–Austrian–Swiss ALL-BFM Study Group Blood 2000 95: 3310–3322

    CAS  PubMed  Google Scholar 

  12. Pui CH, Costlow ME, Kalwinsky DK, Dahl GV . Glucocorticoid receptors in childhood acute non-lymphocytic leukemia Leuk Res 1983 7: 11–16

    Article  CAS  PubMed  Google Scholar 

  13. Sousa AR, Lane SJ, Cidlowski JA, Staynov DZ, Lee TH . Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor beta-isoform J Allergy Clin Immunol 2000 105: 943–950

    Article  CAS  PubMed  Google Scholar 

  14. Shahidi H, Vottero A, Stratakis CA, Taymans SE, Karl M, Longui CA, Chrousos GP, Daughaday WH, Gregory SA, Plate JM . Imbalanced expression of the glucocorticoid receptor isoforms in cultured lymphocytes from a patient with systemic glucocorticoid resistance and chronic lymphocytic leukemia Biochem Biophys Res Commun 1999 254: 559–565

    Article  CAS  PubMed  Google Scholar 

  15. Koper JW, Stolk RP, de Lange P, Huizenga NA, Molijn GJ, Pols HA, Grobbee DE, Karl M, de Jong FH, Brinkmann AO, Lamberts SW . Lack of association between five polymorphisms in the human glucocorticoid receptor gene and glucocorticoid resistance Hum Genet 1997 99: 663–668

    Article  CAS  PubMed  Google Scholar 

  16. Anderer G, Schrappe M, Brechlin AM, Lauten M, Muti P, Welte K, Stanulla M . Polymorphisms within glutathione S-transferase genes and initial response to glucocorticoids in childhood acute lymphoblastic leukaemia Pharmacogenetics 2000 10: 715–726

    Article  CAS  PubMed  Google Scholar 

  17. Dittmar KD, Pratt WB . Folding of the glucocorticoid receptor by the reconstituted Hsp90-based chaperone machinery. The initial hsp90.p60.hsp70-dependent step is sufficient for creating the steroid binding conformation J Biol Chem 1997 272: 13047–13054

    Article  CAS  PubMed  Google Scholar 

  18. Bazzoni F, Beutler B . The tumor necrosis factor ligand and receptor families N Engl J Med 1996 334: 1717–1725

    Article  CAS  PubMed  Google Scholar 

  19. Warzocha K, Bienvenu J, Coiffier B, Salles G . Mechanisms of action of the tumor necrosis factor and lymphotoxin ligand-receptor system Eur Cytokine Netw 1995 6: 83–96

    CAS  PubMed  Google Scholar 

  20. Franchimont D, Martens H, Hagelstein MT, Louis E, Dewe W, Chrousos GP, Belaiche J, Geenen V . Tumor necrosis factor alpha decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone: potential regulation of the glucocorticoid receptor J Clin Endocrinol Metab 1999 84: 2834–2839

    CAS  PubMed  Google Scholar 

  21. Wilson AG, di Giovine FS, Blakemore AI, Duff GW . Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by NcoI restriction of PCR product Hum Mol Genet 1992 1: 353

    Article  CAS  PubMed  Google Scholar 

  22. Abraham LJ, Kroeger KM . Impact of the -308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease J Leukoc Biol 1999 66: 562–566

    Article  CAS  PubMed  Google Scholar 

  23. Wilson AG, di Giovine FS, Duff GW . Genetics of tumour necrosis factor-alpha in autoimmune, infectious, and neoplastic diseases J Inflamm 1995 45: 1–12

    CAS  PubMed  Google Scholar 

  24. Nadel S, Newport MJ, Booy R, Levin M . Variation in the tumor necrosis factor-alpha gene promoter region may be associated with death from meningococcal disease J Infect Dis 1996 174: 878–880

    Article  CAS  PubMed  Google Scholar 

  25. Warzocha K, Bienvenu J, Ribeiro P, Moullet I, Dumontet C, Neidhardt-Berard EM, Coiffier B, Salles G . Plasma levels of tumour necrosis factor and its soluble receptors correlate with clinical features and outcome of Hodgkin's disease patients Br J Cancer 1998 77: 2357–2362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Warzocha K, Ribeiro P, Bienvenu J, Roy P, Charlot C, Rigal D, Coiffier B, Salles G . Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin's lymphoma outcome Blood 1998 91: 3574–3581

    CAS  PubMed  Google Scholar 

  27. Dosquet C, Coudert MC, Lepage E, Cabane J, Richard F . Are angiogenic factors, cytokines, and soluble adhesion molecules prognostic factors in patients with renal cell carcinoma? Clin Cancer Res 1997 3: 2451–2458

    CAS  PubMed  Google Scholar 

  28. Demeter J, Porzsolt F, Ramisch S, Schmidt D, Schmid M, Messer G . Polymorphism of the tumour necrosis factor-alpha and lymphotoxin-alpha genes in chronic lymphocytic leukaemia Br J Haematol 1997 97: 107–112

    Article  CAS  PubMed  Google Scholar 

  29. Sankaran D, Asderakis A, Ashraf S, Roberts IS, Short CD, Dyer PA, Sinnott PJ, Hutchinson IV . Cytokine gene polymorphisms predict acute graft rejection following renal transplantation Kidney Int 1999 56: 281–288

    Article  CAS  PubMed  Google Scholar 

  30. Khatri VP, Caligiuri MA . A review of the association between interleukin-10 and human B-cell malignancies Cancer Immunol Immunother 1998 46: 239–244

    Article  CAS  PubMed  Google Scholar 

  31. Klein B, Lu ZY, Gu ZJ, Costes V, Jourdan M, Rossi JF . Interleukin-10 and Gp130 cytokines in human multiple myeloma Leuk Lymphoma 1999 34: 63–70

    Article  CAS  PubMed  Google Scholar 

  32. Middleton PG, Taylor PR, Jackson G, Proctor SJ, Dickinson AM . Cytokine gene polymorphisms associating with severe acute graft-versus-host disease in HLA-identical sibling transplants Blood 1998 92: 3943–3948

    CAS  PubMed  Google Scholar 

  33. Edwards-Smith CJ, Jonsson JR, Purdie DM, Bansal A, Shorthouse C, Powell EE . Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa Hepatology 1999 30: 526–530

    Article  CAS  PubMed  Google Scholar 

  34. Huang DR, Zhou YH, Xia SQ, Liu L, Pirskanen R, Lefvert AK . Markers in the promoter region of interleukin-10 (IL-10) gene in myasthenia gravis: implications of diverse effects of IL-10 in the pathogenesis of the disease J Neuroimmunol 1999 94: 82–87

    Article  CAS  PubMed  Google Scholar 

  35. Tagore A, Gonsalkorale WM, Pravica V, Hajeer AH, McMahon R, Whorwell PJ, Sinnott PJ, Hutchinson IV . Interleukin-10 (IL-10) genotypes in inflammatory bowel disease Tissue Antigens 1999 54: 386–390

    Article  CAS  PubMed  Google Scholar 

  36. Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P . Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis Arthritis Rheum 1999 42: 1101–1108

    Article  CAS  PubMed  Google Scholar 

  37. Eskdale J, McNicholl J, Wordsworth P, Jonas B, Huizinga T, Field M, Gallagher G . Interleukin-10 microsatellite polymorphisms and IL-10 locus alleles in rheumatoid arthritis susceptibility Lancet 1998 352: 1282–1283

    Article  CAS  PubMed  Google Scholar 

  38. Coakley G, Mok CC, Hajeer AH, Ollier WE, Turner D, Sinnott PJ, Hutchinson IV, Panayi GS, Lanchbury JS . Interleukin-10 promoter polymorphisms in rheumatoid arthritis and Felty's syndrome Br J Rheumatol 1998 37: 988–991

    Article  CAS  PubMed  Google Scholar 

  39. Lazarus M, Hajeer AH, Turner D, Sinnott P, Worthington J, Ollier WE, Hutchinson IV . Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus J Rheumatol 1997 24: 2314–2317

    CAS  PubMed  Google Scholar 

  40. Fayad L, Keating MJ, Reuben JM, O'Brien S, Lee BN, Lerner S, Kurzrock R . Interleukin-6 and interleukin-10 levels in chronic lymphocytic leukemia: correlation with phenotypic characteristics and outcome Blood 2001 97: 256–263

    Article  CAS  PubMed  Google Scholar 

  41. Rosenwasser LJ, Borish L . Genetics of atopy and asthma: the rationale behind promoter-based candidate gene studies (IL-4 and IL-10) Am J Respir Crit Care Med 1997 156: S152–155

    Article  CAS  PubMed  Google Scholar 

  42. Hobbs K, Negri J, Klinnert M, Rosenwasser LJ, Borish L . Interleukin-10 and transforming growth factor-beta promoter polymorphisms in allergies and asthma Am J Respir Crit Care Med 1998 158: 1958–1962

    Article  CAS  PubMed  Google Scholar 

  43. Hurme M, Lahdenpohja N, Santtila S . Gene polymorphisms of interleukins 1 and 10 in infectious and autoimmune diseases Ann Med 1998 30: 469–473

    Article  CAS  PubMed  Google Scholar 

  44. Turner D, Grant SC, Yonan N, Sheldon S, Dyer PA, Sinnott PJ, Hutchinson IV . Cytokine gene polymorphism and heart transplant rejection Transplantation 1997 64: 776–779

    Article  CAS  PubMed  Google Scholar 

  45. Bathgate AJ, Pravica V, Perrey C, Therapondos G, Plevris JN, Hayes PC, Hutchinson IV . The effect of polymorphisms in tumor necrosis factor-alpha, interleukin-10, and transforming growth factor-beta1 genes in acute hepatic allograft rejection Transplantation 2000 69: 1514–1517

    Article  CAS  PubMed  Google Scholar 

  46. Stanulla M, Schrauder A, Welte K, Schrappe M . Tumor necrosis factor and lymphotoxin-alpha genetic polymorphisms and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia: a case-control study of patients treated with BFM therapy BMC Blood Disorders 2001 1: 2

    PubMed  PubMed Central  Google Scholar 

  47. Reiter A, Schrappe M, Ludwig WD, Hiddemann W, Sauter S, Henze G, Zimmermann M, Lampert F, Havers W, Niethammer D . Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86 Blood 1994 84: 3122–3133

    CAS  PubMed  Google Scholar 

  48. Eskdale J, Kube D, Tesch H, Gallagher G . Mapping of the human IL10 gene and further characterization of the 5′ flanking sequence Immunogenetics 1997 46: 120–128

    Article  CAS  PubMed  Google Scholar 

  49. Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV . An investigation of polymorphism in the interleukin-10 gene promoter Eur J Immunogenet 1997 24: 1–8

    Article  CAS  PubMed  Google Scholar 

  50. Donaldson PT, Norris S, Constantini PK, Bernal W, Harrison P, Williams R . The interleukin-1 and interleukin-10 gene polymorphisms in primary sclerosing cholangitis: no associations with disease susceptibility/resistance J Hepatol 2000 32: 882–886

    Article  CAS  PubMed  Google Scholar 

  51. Cavet J, Middleton PG, Segall M, Noreen H, Davies SM, Dickinson AM . Recipient tumor necrosis factor-alpha and interleukin-10 gene polymorphisms associate with early mortality and acute graft-versus-host disease severity in HLA-matched sibling bone marrow transplants Blood 1999 94: 3941–3946

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank all the participants of the ALL-BFM 86 and 90 studies as well as all doctors and nurses of participating medical centres for their excellent cooperation. This study was partly supported by: Madeleine-Schickedanz-Kinderkrebsstiftung, Fürth, Germany and Erich und Emmy Hoselmann-Stiftung, Hannover, Germany.

Author information

Authors and Affiliations

  1. Department of Paediatric Haematology and Oncology, Hannover Medical School, Children's Hospital, Hannover, Germany

    M Lauten, T Matthias, M Stanulla, C Beger, K Welte & M Schrappe

Authors
  1. M Lauten
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Matthias
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Stanulla
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Beger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Welte
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Schrappe
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lauten, M., Matthias, T., Stanulla, M. et al. 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 16, 1437–1442 (2002). https://doi.org/10.1038/sj.leu.2402545

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402545

Keywords

This article is cited by

Search

Advanced search

Quick links