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Acute Leukemias

The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia

Abstract

Loss of p53—a tumor suppressor gene located on the short arm of chromosome 17 (band 17p13.1)—was detected in 105 out of 2272 (5%) adult acute myeloid leukemia (AML) patients who took part in the Study Alliance Leukemia AML96 and AML2003 multi center trials. There were 85 patients with 17p (p53) deletion with multiple aberrations and 20 patients with a 17p (p53) deletion as single aberration or with only one additional chromosomal abnormality. None of the p53-deleted patients displayed additional low-risk aberrations, like t(8;21) or inv(16). Significant positive association between p53 deletion and other high-risk factors was identified for del(5q) (P<0.001), −5 (P<0.001) and −7 (P<0.05). The molecular risk factors FLT3-ITD and NPM1 mutation showed an inverse correlation to the p53 deletion in complex aberrant patients (P<0.001). The multivariate analysis revealed p53 deletion without multiple aberrations as an independent negative prognostic factor for disease-free survival (P<0.001), relapse risk (P=0.028) and overall survival (P<0.001). Thus, the single p53 deletion should be considered as a high-risk aberration for future risk-adapted treatment strategies in AML.

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References

  1. Fenaux P, Preudhomme C, Lai JL, Morel P, Beuscart R, Bauters F . Cytogenetics and their prognostic value in de novo acute myeloid leukaemia: a report on 283 cases. Br J Haematol 1989; 73: 61–67.

    Article  CAS  PubMed  Google Scholar 

  2. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 1998; 92: 2322–2333.

    CAS  PubMed  Google Scholar 

  3. Mrozek K, Heinonen K, Bloomfield CD . Prognostic value of cytogenetic findings in adults with acute myeloid leukemia. Int J Hematol 2000; 72: 261–271.

    CAS  PubMed  Google Scholar 

  4. Grimwade D, Walker H, Harrison G, Oliver F, Chatters S, Harrison CJ et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 2001; 98: 1312–1320.

    Article  CAS  PubMed  Google Scholar 

  5. Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100: 4325–4336.

    CAS  PubMed  Google Scholar 

  6. Haferlach T, Kern W, Schoch C, Schnittger S, Sauerland MC, Heinecke A et al. A new prognostic score for patients with acute myeloid leukemia based on cytogenetics and early blast clearance in trials of the German AML Cooperative Group. Haematologica 2004; 89: 408–418.

    PubMed  Google Scholar 

  7. Soenen V, Preudhomme C, Roumier C, Daudignon A, Lai JL, Fenaux P . 17p Deletion in acute myeloid leukemia and myelodysplastic syndrome. Analysis of breakpoints and deleted segments by fluorescence in situ. Blood 1998; 91: 1008–1015.

    CAS  PubMed  Google Scholar 

  8. Vousden KH, Lu X . Live or let die: the cell's response to p53. Nat Rev Cancer 2002; 2: 594–604.

    Article  CAS  PubMed  Google Scholar 

  9. Sander CA, Yano T, Clark HM, Harris C, Longo DL, Jaffe ES et al. p53 mutation is associated with progression in follicular lymphomas. Blood 1993; 82: 1994–2004.

    CAS  PubMed  Google Scholar 

  10. Nakai H, Misawa S, Taniwaki M, Horiike S, Takashima T, Seriu T et al. Prognostic significance of loss of a chromosome 17p and p53 gene mutations in blast crisis of chronic myelogenous leukaemia. Br J Haematol 1994; 87: 425–427.

    Article  CAS  PubMed  Google Scholar 

  11. Dohner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 1995; 85: 1580–1589.

    CAS  PubMed  Google Scholar 

  12. Fenaux P, Preudhomme C, Lai JL, Quiquandon I, Jonveaux P, Vanrumbeke M et al. Mutations of the p53 gene in B-cell chronic lymphocytic leukemia: a report on 39 cases with cytogenetic analysis. Leukemia 1992; 6: 246–250.

    CAS  PubMed  Google Scholar 

  13. Haferlach C, Dicker F, Herholz H, Schnittger S, Kern W, Haferlach T . Mutations of the TP53 gene in acute myeloid leukemia are strongly associated with a complex aberrant karyotype. Leukemia 2008; 22: 1539–1541.

    Article  CAS  PubMed  Google Scholar 

  14. Schoch C, Haferlach T, Bursch S, Gerstner D, Schnittger S, Dugas M et al. Loss of genetic material is more common than gain in acute myeloid leukemia with complex aberrant karyotype: a detailed analysis of 125 cases using conventional chromosome analysis and fluorescence in situ hybridization including 24-color FISH. Genes Chromosomes Cancer 2002; 35: 20–29.

    Article  PubMed  Google Scholar 

  15. Schoch C, Kern W, Kohlmann A, Hiddemann W, Schnittger S, Haferlach T . Acute myeloid leukemia with a complex aberrant karyotype is a distinct biological entity characterized by genomic imbalances and a specific gene expression profile. Genes Chromosomes Cancer 2005; 43: 227–238.

    Article  CAS  PubMed  Google Scholar 

  16. van der Holt B, Breems DA, Berna Beverloo H, van den Berg E, Burnett AK, Sonneveld P et al. Various distinctive cytogenetic abnormalities in patients with acute myeloid leukaemia aged 60 years and older express adverse prognostic value: results from a prospective clinical trial. Br J Haematol 2007; 136: 96–105.

    Article  PubMed  Google Scholar 

  17. Wattel E, Preudhomme C, Hecquet B, Vanrumbeke M, Quesnel B, Dervite I et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 1994; 84: 3148–3157.

    CAS  PubMed  Google Scholar 

  18. Nakano Y, Naoe T, Kiyoi H, Kitamura K, Minami S, Miyawaki S et al. Prognostic value of p53 gene mutations and the product expression in de novo acute myeloid leukemia. Eur J Haematol 2000; 65: 23–31.

    Article  CAS  PubMed  Google Scholar 

  19. Kurosawa M, Okabe M, Kunieda Y, Asaka M . Analysis of the p53 gene mutations in acute myelogenous leukemia: the p53 gene mutations associated with a deletion of chromosome 17. Ann Hematol 1995; 71: 83–87.

    Article  CAS  PubMed  Google Scholar 

  20. Melo MB, Ahmad NN, Lima CS, Pagnano KB, Bordin S, Lorand-Metze I et al. Mutations in the p53 gene in acute myeloid leukemia patients correlate with poor prognosis. Hematology 2002; 7: 13–19.

    Article  CAS  PubMed  Google Scholar 

  21. Christiansen DH, Andersen MK, Pedersen-Bjergaard J . Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. J Clin Oncol 2001; 19: 1405–1413.

    Article  CAS  PubMed  Google Scholar 

  22. Nahi H, Lehmann S, Bengtzen S, Jansson M, Mollgard L, Paul C et al. Chromosomal aberrations in 17p predict in vitro drug resistance and short overall survival in acute myeloid leukemia. Leuk Lymphoma 2008; 49: 508–516.

    Article  CAS  PubMed  Google Scholar 

  23. Schaich M, Ritter M, Illmer T, Lisske P, Thiede C, Schakel U et al. Mutations in ras proto-oncogenes are associated with lower mdr1 gene expression in adult acute myeloid leukaemia. Br J Haematol 2001; 112: 300–307.

    Article  CAS  PubMed  Google Scholar 

  24. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003; 21: 4642–4649.

    Article  PubMed  Google Scholar 

  25. Shaffer LG, Tommerup N (eds). ISCN (2005): An International System for Human Cytogenetic Nomenclature. S Karger: Basel, Switzerland, 2005.

    Google Scholar 

  26. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000; 96: 4075–4083.

    CAS  PubMed  Google Scholar 

  27. Kastan MB, Radin AI, Kuerbitz SJ, Onyekwere O, Wolkow CA, Civin CI et al. Levels of p53 protein increase with maturation in human hematopoietic cells. Cancer Res 1991; 51: 4279–4286.

    CAS  PubMed  Google Scholar 

  28. Takeda K, Minowada J, Bloch A . Kinetics of appearance of differentiation-associated characteristics in ML-1, a line of human myeloblastic leukemia cells, after treatment with 12-O-tetradecanoylphorbol-13-acetate, dimethyl sulfoxide or 1-beta-D-arabinofuranosylcytosine. Cancer Res 1982; 42: 5152–5158.

    CAS  PubMed  Google Scholar 

  29. Castro PD, Liang JC, Nagarajan L . Deletions of chromosome 5q13.3 and 17p loci cooperate in myeloid neoplasms. Blood 2000; 95: 2138–2143.

    CAS  PubMed  Google Scholar 

  30. Horiike S, Misawa S, Kaneko H, Sasai Y, Kobayashi M, Fujii H et al. Distinct genetic involvement of the TP53 gene in therapy-related leukemia and myelodysplasia with chromosomal losses of Nos 5 and/or 7 and its possible relationship to replication error phenotype. Leukemia 1999; 13: 1235–1242.

    Article  CAS  PubMed  Google Scholar 

  31. Fioretos T, Strombeck B, Sandberg T, Johansson B, Billstrom R, Borg A et al. Isochromosome 17q in blast crisis of chronic myeloid leukemia and in other hematologic malignancies is the result of clustered breakpoints in 17p11 and is not associated with coding TP53 mutations. Blood 1999; 94: 225–232.

    CAS  PubMed  Google Scholar 

  32. Fenaux P, Jonveaux P, Quiquandon I, Lai JL, Pignon JM, Loucheux-Lefebvre MH et al. P53 gene mutations in acute myeloid leukemia with 17p monosomy. Blood 1991; 78: 1652–1657.

    CAS  PubMed  Google Scholar 

  33. Lai JL, Preudhomme C, Zandecki M, Flactif M, Vanrumbeke M, Lepelley P et al. Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoiesis and a high incidence of P53 mutations. Leukemia 1995; 9: 370–381.

    CAS  PubMed  Google Scholar 

  34. Venkatachalam S, Shi YP, Jones SN, Vogel H, Bradley A, Pinkel D et al. Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation. EMBO J 1998; 17: 4657–4667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Watanabe T, Hotta T, Ichikawa A, Kinoshita T, Nagai H, Uchida T et al. The MDM2 oncogene overexpression in chronic lymphocytic leukemia and low-grade lymphoma of B-cell origin. Blood 1994; 84: 3158–3165.

    CAS  PubMed  Google Scholar 

  36. Sankar M, Tanaka K, Kumaravel TS, Arif M, Shintani T, Yagi S et al. Identification of a commonly deleted region at 17p13.3 in leukemia and lymphoma associated with 17p abnormality. Leukemia 1998; 12: 510–516.

    Article  CAS  PubMed  Google Scholar 

  37. Schaich M, Soucek S, Thiede C, Ehninger G, Illmer T . MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia. Br J Haematol 2005; 128: 324–332.

    Article  CAS  PubMed  Google Scholar 

  38. Cavalcanti Jr GB, da Cunha Vasconcelos F, Pinto de Faria G, Scheiner MA, de Almeida Dobbin J, Klumb CE et al. Coexpression of p53 protein and MDR functional phenotype in leukemias: the predominant association in chronic myeloid leukemia. Cytometry B Clin Cytom 2004; 61: 1–8.

    Article  PubMed  Google Scholar 

  39. Nahi H, Merup M, Lehmann S, Bengtzen S, Mollgard L, Selivanova G et al. PRIMA-1 induces apoptosis in acute myeloid leukaemia cells with p53 gene deletion. Br J Haematol 2006; 132: 230–236.

    Article  CAS  PubMed  Google Scholar 

  40. Nahi H, Selivanova G, Lehmann S, Mollgard L, Bengtzen S, Concha H et al. Mutated and non-mutated TP53 as targets in the treatment of leukaemia. Br J Haematol 2008; 141: 445–453.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the following physicians and participating centers of the SAL study group who entered their patients into the trials: W Siegert, O Rick (Universitätsklinikum Charité Mitte, Berlin); E Thiel (Universitätsklinikum Benjamin Franklin, Berlin); E Späth-Schwalbe, S Hesse-Amojo (Vivantes Klinikum Spandau, Berlin); R Kolloch, U Krümpelmann (Krankenanstalten Gilead, Bielefeld); M Görner, S Probst (Klinikum Mitte, Bielefeld); K-H Pflüger, T Wolff (Ev. Diakonie-Krankenhaus, Bremen); H Heidtmann, L Kalcki (St Joseph Hospital, Bremerhaven); J Hotz, F Marquard (Allgemeines Krankenhaus Celle, Celle); M Hänel, R Herbst (Krankenhaus Küchwald, Chemnitz); G Ehninger, M Schaich (Universitätsklinikum, Dresden); M Grammatzki, G Helm (Universitätsklinikum, Erlangen); JG Saal (Malteser Krankenhaus, Flensburg); H-G Höffkes, M Arland (Klinikum Fulda, Fulda); E Fasshauer, B Opitz (Krankenhaus St Elisabeth und St Barbara, Halle); R Kuse, N Schmitz, R Stuhlmann (Allg. Krankenhaus St Georg, Hamburg); H Schmidt, K Buhrmann (Kreiskrankenhaus, Hameln); H Dürk, B Bechtel (St Marien-Hospital, Hamm); R Teschke, M Burk (Klinikum Stadt, Hanau); A Ho (Universitätsklinikum, Heidelberg); U Kaiser, A Bartholomäus (St Bernward Krankenhaus, Hildesheim); AA Fauser, S Zimber (Klinik für Knochenmarktransplantation und Hämatologie/Onkologie, Idar-Oberstein); H Link, F-G Hagmann (Westpfalz-Klinikum, Kaiserslautern); L Mantovani (Städtisches Klinikum St Georg, Leipzig); K-P Schalk (St Vincent Krankenhaus, Limburg/Lahn); S Fetscher (Sana Kliniken Lübeck, Lübeck); T Wagner (Universitätsklinikum Lübeck, Lübeck); A Neubauer (Universitätsklinikum, Marburg); H Bodenstein, J Tischler (Klinikum Minden, Minden); R Hartenstein, N Brack, H Pohlmann (Krankenhaus München-Harlaching, München); W Wilhelm, H Wandt, K Schäfer-Eckardt (Klinikum Nord, Nürnberg); H Dancygier, B Seeber (Klinikum Offenbach, Offenbach am Main); F Hirsch, I Dressel (Klinikum Offenburg, Offenburg); H Heißmeyer, T Geer (Diakonie-Krankenhaus, Schwäbisch-Hall); E Jähde, J Labenz (Ev. Jung-Stilling Krankenhaus, Siegen); W Aulitzky, L Leimer (Robert-Bosch-Krankenhaus, Stuttgart); E Heidemann, J Kaesberger (Diakonissenkrankenhaus, Stuttgart); MR Clemens, R Mahlberg (Krankenanstalt Mutterhaus der Borromäerinnen, Trier); R Schwerdtfeger (Deutsche Klinik für Diagnostik, Wiesbaden); R Engberding, R Winter (Stadtkrankenhaus Wolfsburg, Wolfsburg); K Wilms, H Rücke-Lanz, F Weissinger (Universitätsklinikum, Würzburg); M Sandmann, A Hellmann (Kliniken St Antonius, Wuppertal).

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Seifert, H., Mohr, B., Thiede, C. et al. The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia. Leukemia 23, 656–663 (2009). https://doi.org/10.1038/leu.2008.375

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