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Sensitivity and Resistance to Therapy

WT1 mutations are secondary events in AML, show varying frequencies and impact on prognosis between genetic subgroups

Leukemia volume 29, pages 660–667 (2015)Cite this article

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Abstract

To investigate frequency and prognostic impact of Wilms tumor 1 (WT1) mutations (mut), we analyzed 3157 unselected acute myeloid leukemia patients for WT1mut in exons 7 and 9. In total, 188 WT1 mutations were detected (exon 7: n=150, exon 9: n=38); 141 were frameshift, 24 missense, 14 non-sense, 7 splice site and 2 indel mutations. In 175/3157 (5.5%) patients, a WT1mut was found. Higher frequencies were detected in patients with biallelic CEBPAmut (13.6%; P=0.001), followed by t(15;17)/PML-RARA (11.0%, P=0.004), and FLT3-ITD (8.5%, P<0.001). WT1mut were rare in DNMT3Amut (4.4%, P=0.014), ASXL1mut (1.7%, P<0.001), IDH2R140 (1.7%, P=0.001) and IDH1R132 (0.9%, P<0.001), and not detected in complex karyotypes (P=0.047). They were more frequent in females than in males (6.6 vs 4.7%; P=0.014) and in patients <60 years (P<0.001). Analysis of paired samples of 35 patients revealed a relatively unstable character of WT1mut (65.7% retained, 34.3% lost WT1mut at relapse). In the total cohort and subgroups with high WT1mut incidences (biallelic CEBPAmut, PML-RARA), WT1mut had no impact on prognosis. In normal karyotype AML, WT1mut patients had shorter event-free survival (EFS) (10.8 vs 17.9 m, P=0.008). In multivariate analysis, WT1mut had an independent adverse impact on EFS (P=0.002, hazard ratio (HR): 1.64) besides FLT3-ITD status (P<0.001, HR: 1.71) and age (P<0.001, HR: 1.28).

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References

  1. 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.

    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. 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 

  4. Mrozek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD . Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood 2007; 109: 431–448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Marcucci G, Maharry K, Whitman SP, Vukosavljevic T, Paschka P, Langer C et al. High expression levels of the ETS-related gene, ERG, predict adverse outcome and improve molecular risk-based classification of cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B Study. J Clin Oncol 2007; 25: 3337–3343.

    Article  CAS  PubMed  Google Scholar 

  6. Miller CA, Wilson RK, Ley TJ . Genomic landscapes and clonality of de novo AML. N Engl J Med 2013; 369: 1473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sugiyama H . Wilms' tumor gene WT1: its oncogenic function and clinical application. Int J Hematol 2001; 73: 177–187.

    Article  CAS  PubMed  Google Scholar 

  8. Inoue K, Sugiyama H, Ogawa H, Nakagawa M, Yamagami T, Miwa H et al. WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood 1994; 84: 3071–3079.

    CAS  PubMed  Google Scholar 

  9. Inoue K, Ogawa H, Yamagami T, Soma T, Tani Y, Tatekawa T et al. Long-term follow-up of minimal residual disease in leukemia patients by monitoring WT1 (Wilms tumor gene) expression levels. Blood 1996; 88: 2267–2278.

    CAS  PubMed  Google Scholar 

  10. Inoue K, Ogawa H, Sonoda Y, Kimura T, Sakabe H, Oka Y et al. Aberrant overexpression of the Wilms tumor gene (WT1) in human leukemia. Blood 1997; 89: 1405–1412.

    CAS  PubMed  Google Scholar 

  11. Cilloni D, Gottardi E, De Micheli D, Serra A, Volpe G, Messa F et al. Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients. Leukemia 2002; 16: 2115–2121.

    Article  CAS  PubMed  Google Scholar 

  12. Trka J, Kalinova M, Hrusak O, Zuna J, Krejci O, Madzo J et al. Real-time quantitative PCR detection of WT1 gene expression in children with AML: prognostic significance, correlation with disease status and residual disease detection by flow cytometry. Leukemia 2002; 16: 1381–1389.

    Article  CAS  PubMed  Google Scholar 

  13. Cilloni D, Gottardi E, Fava M, Messa F, Carturan S, Busca A et al. Usefulness of quantitative assessment of the WT1 gene transcript as a marker for minimal residual disease detection. Blood 2003; 102: 773–774.

    Article  CAS  PubMed  Google Scholar 

  14. Garg M, Moore H, Tobal K, Liu Yin JA . Prognostic significance of quantitative analysis of WT1 gene transcripts by competitive reverse transcription polymerase chain reaction in acute leukaemia. Br J Haematol 2003; 123: 49–59.

    Article  CAS  PubMed  Google Scholar 

  15. Ogawa H, Tamaki H, Ikegame K, Soma T, Kawakami M, Tsuboi A et al. The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemia. Blood 2003; 101: 1698–1704.

    Article  CAS  PubMed  Google Scholar 

  16. Ostergaard M, Olesen LH, Hasle H, Kjeldsen E, Hokland P . WT1 gene expression: an excellent tool for monitoring minimal residual disease in 70% of acute myeloid leukaemia patients - results from a single-centre study. Br J Haematol 2004; 125: 590–600.

    Article  CAS  PubMed  Google Scholar 

  17. Weisser M, Kern W, Rauhut S, Schoch C, Hiddemann W, Haferlach T et al. Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia. Leukemia 2005; 19: 1416–1423.

    Article  CAS  PubMed  Google Scholar 

  18. Lapillonne H, Renneville A, Auvrignon A, Flamant C, Blaise A, Perot C et al. High WT1 expression after induction therapy predicts high risk of relapse and death in pediatric acute myeloid leukemia. J Clin Oncol 2006; 24: 1507–1515.

    Article  CAS  PubMed  Google Scholar 

  19. Cilloni D, Messa F, Arruga F, Defilippi I, Gottardi E, Fava M et al. Early prediction of treatment outcome in acute myeloid leukemia by measurement of WT1 transcript levels in peripheral blood samples collected after chemotherapy. Haematologica 2008; 93: 921–924.

    Article  PubMed  Google Scholar 

  20. Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 1990; 60: 509–520.

    Article  CAS  PubMed  Google Scholar 

  21. Yang L, Han Y, Suarez SF, Minden MD . A tumor suppressor and oncogene: the WT1 story. Leukemia 2007; 21: 868–876.

    Article  CAS  PubMed  Google Scholar 

  22. Haber DA, Buckler AJ, Glaser T, Call KM, Pelletier J, Sohn RL et al. An internal deletion within an 11p13 zinc finger gene contributes to the development of Wilms' tumor. Cell 1990; 61: 1257–1269.

    Article  CAS  PubMed  Google Scholar 

  23. Yamagami T, Sugiyama H, Inoue K, Ogawa H, Tatekawa T, Hirata M et al. Growth inhibition of human leukemic cells by WT1 (Wilms tumor gene) antisense oligodeoxynucleotides: implications for the involvement of WT1 in leukemogenesis. Blood 1996; 87: 2878–2884.

    CAS  PubMed  Google Scholar 

  24. Nishida S, Hosen N, Shirakata T, Kanato K, Yanagihara M, Nakatsuka S et al. AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene, WT1. Blood 2006; 107: 3303–3312.

    Article  CAS  PubMed  Google Scholar 

  25. Ariyaratana S, Loeb DM . The role of the Wilms tumour gene (WT1) in normal and malignant haematopoiesis. Expert Rev Mol Med 2007; 9: 1–17.

    Article  PubMed  Google Scholar 

  26. Bergmann L, Miething C, Maurer U, Brieger J, Karakas T, Weidmann E et al. High levels of Wilms' tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood 1997; 90: 1217–1225.

    CAS  PubMed  Google Scholar 

  27. Barragan E, Cervera J, Bolufer P, Ballester S, Martin G, Fernandez P et al. Prognostic implications of Wilms' tumor gene (WT1) expression in patients with de novo acute myeloid leukemia. Haematologica 2004; 89: 926–933.

    CAS  PubMed  Google Scholar 

  28. Rodrigues PC, Oliveira SN, Viana MB, Matsuda EI, Nowill AE, Brandalise SR et al. Prognostic significance of WT1 gene expression in pediatric acute myeloid leukemia. Pediatr Blood Cancer 2007; 49: 133–138.

    Article  PubMed  Google Scholar 

  29. Paschka P, Marcucci G, Ruppert AS, Whitman SP, Mrozek K, Maharry K et al. Wilms Tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B Study. J Clin Oncol 2008; 26: 4595–4602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Renneville A, Boissel N, Zurawski V, Llopis L, Biggio V, Nibourel O et al. Wilms tumor 1 gene mutations are associated with a higher risk of recurrence in young adults with acute myeloid leukemia: a study from the Acute Leukemia French Association. Cancer 2009; 115: 3719–3727.

    Article  CAS  PubMed  Google Scholar 

  31. Gaidzik VI, Schlenk RF, Moschny S, Becker A, Bullinger L, Corbacioglu A et al. Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia: a study of the German-Austrian AML Study Group. Blood 2009; 113: 4505–4511.

    Article  CAS  PubMed  Google Scholar 

  32. Summers K, Stevens J, Kakkas I, Smith M, Smith LL, Macdougall F et al. Wilms' tumour 1 mutations are associated with FLT3-ITD and failure of standard induction chemotherapy in patients with normal karyotype AML. Leukemia 2007; 21: 550–551.

    Article  CAS  PubMed  Google Scholar 

  33. Virappane P, Gale R, Hills R, Kakkas I, Summers K, Stevens J et al. Mutation of the Wilms' tumor 1 gene is a poor prognostic factor associated with chemotherapy resistance in normal karyotype acute myeloid leukemia: the United Kingdom Medical Research Council Adult Leukaemia Working Party. J Clin Oncol 2008; 26: 5429–5435.

    Article  CAS  PubMed  Google Scholar 

  34. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 2002; 100: 59–66.

    Article  CAS  PubMed  Google Scholar 

  35. Roller A, Grossmann V, Bacher U, Poetzinger F, Weissmann S, Nadarajah N et al. Landmark analysis of DNMT3A mutations in hematological malignancies. Leukemia 2013; 27: 1573–1578.

    Article  CAS  PubMed  Google Scholar 

  36. Bacher U, Haferlach C, Kern W, Haferlach T, Schnittger S . Prognostic relevance of FLT3-TKD mutations in AML: the combination matters–an analysis of 3082 patients. Blood 2008; 111: 2527–2537.

    Article  CAS  PubMed  Google Scholar 

  37. Schnittger S, Haferlach C, Ulke M, Alpermann T, Kern W, Haferlach T . IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. Blood 2010; 116: 5486–5496.

    Article  CAS  PubMed  Google Scholar 

  38. Schnittger S, Bacher U, Kern W, Schröder M, Haferlach T, Schoch C . Report on two novel nucleotide exchanges in the JAK2 pseudokinase domain: D620E and E627E. Leukemia 2006; 20: 2195–2197.

    Article  CAS  PubMed  Google Scholar 

  39. Schnittger S, Kohl TM, Haferlach T, Kern W, Hiddemann W, Spiekermann K et al. KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 2006; 107: 1791–1799.

    Article  CAS  PubMed  Google Scholar 

  40. Bacher U, Haferlach T, Schoch C, Kern W, Schnittger S . Implications of NRAS mutations in AML: a study of 2502 patients. Blood 2006; 107: 3847–3853.

    Article  CAS  PubMed  Google Scholar 

  41. Schnittger S, Schoch C, Kern W, Mecucci C, Tschulik C, Martelli MF et al. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 2005; 106: 3733–3739.

    Article  CAS  PubMed  Google Scholar 

  42. Schnittger S, Kern W, Tschulik C, Weiss T, Dicker F, Falini B et al. Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML. Blood 2009; 114: 2220–2231.

    Article  CAS  PubMed  Google Scholar 

  43. Weisser M, Kern W, Schoch C, Hiddemann W, Haferlach T, Schnittger S . Risk assessment by monitoring expression levels of partial tandem duplications in the MLL gene in acute myeloid leukemia during therapy. Haematologica 2005; 90: 881–889.

    CAS  PubMed  Google Scholar 

  44. Weissmann S, Alpermann T, Grossmann V, Kowarsch A, Nadarajah N, Eder C et al. Landscape of TET2 mutations in acute myeloid leukemia. Leukemia 2012; 26: 934–942.

    Article  CAS  PubMed  Google Scholar 

  45. Grossmann V, Schnittger S, Kohlmann A, Eder C, Roller A, Dicker F et al. A novel hierarchical prognostic model of AML solely based on molecular mutations. Blood 2012; 120: 2963–2972.

    Article  CAS  PubMed  Google Scholar 

  46. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 1976; 33: 451–458.

    Article  CAS  PubMed  Google Scholar 

  47. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 1985; 103: 620–625.

    Article  CAS  PubMed  Google Scholar 

  48. Arber DA, Brunning RD, Le Beau MM, Falini B, Vardiman J, Porwit A et al. Acute myeloid leukemia with recurrent genetic abnormalities. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H (eds). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.Lyon: International Agency for Research on Cancer (IARC) 2008; p 110–123.

  49. Schoch C, Schnittger S, Bursch S, Gerstner D, Hochhaus A, Berger U et al. Comparison of chromosome banding analysis, interphase- and hypermetaphase-FISH, qualitative and quantitative PCR for diagnosis and for follow-up in chronic myeloid leukemia: a study on 350 cases. Leukemia 2002; 16: 53–59.

    Article  CAS  PubMed  Google Scholar 

  50. Haferlach C, Rieder H, Lillington DM, Dastugue N, Hagemeijer A, Harbott J et al. Proposals for standardized protocols for cytogenetic analyses of acute leukemias, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorders, and myelodysplastic syndromes. Genes Chromosomes Cancer 2007; 46: 494–499.

    Article  CAS  PubMed  Google Scholar 

  51. Shaffer LG, McGowan-Jordan J, Schmid M . ISCN 2013: An International System for Human Cytogenetic Nomenclature. Karger: Basel, New York, 2013.

    Google Scholar 

  52. Kern W, Voskova D, Schoch C, Hiddemann W, Schnittger S, Haferlach T . Determination of relapse risk based on assessment of minimal residual disease during complete remission by multiparameter flow cytometry in unselected patients with acute myeloid leukemia. Blood 2004; 104: 3078–3085.

    Article  CAS  PubMed  Google Scholar 

  53. Kern W, Bacher U, Haferlach C, Schnittger S, Haferlach T . The role of multiparameter flow cytometry for disease monitoring in AML. Best Pract Res Clin Haematol 2010; 23: 379–390.

    Article  CAS  PubMed  Google Scholar 

  54. Cheson BD, Bennett JM, Kopecky KJ, Buchner 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 

  55. Becker H, Marcucci G, Maharry K, Radmacher MD, Mrozek K, Margeson D et al. Mutations of the Wilms tumor 1 gene (WT1) in older patients with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood 2010; 116: 788–792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ho PA, Zeng R, Alonzo TA, Gerbing RB, Miller KL, Pollard JA et al. Prevalence and prognostic implications of WT1 mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group. Blood 2010; 116: 702–710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hollink IH, van den Heuvel-Eibrink M, Zimmermann M, Balgobind BV, rentsen-Peters ST, Alders M et al. Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia. Blood 2009; 113: 5951–5960.

    Article  CAS  PubMed  Google Scholar 

  58. Schnittger S, Bacher U, Haferlach C, Kern W, Alpermann T, Haferlach T . Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t(15;17)/PML-RARA. Haematologica 2011; 96: 1799–1807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hou HA, Huang TC, Lin LI, Liu CY, Chen CY, Chou WC et al. WT1 mutation in 470 adult patients with acute myeloid leukemia: stability during disease evolution and implication of its incorporation into a survival scoring system. Blood 2010; 115: 5222–5231.

    Article  CAS  PubMed  Google Scholar 

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  1. MLL Munich Leukemia Laboratory, Munich, Germany

    M-T Krauth, T Alpermann, U Bacher, C Eder, F Dicker, M Ulke, S Kuznia, N Nadarajah, W Kern, C Haferlach, T Haferlach & S Schnittger

  2. Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University Vienna, Vienna, Austria

    M-T Krauth

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SS, WK, CH and TH are part owners of the MLL Munich Leukemia Laboratory GmbH. MTK, TA, UB, CE, FD, MU, SK and NN are employed by the MLL Munich Leukemia Laboratory GmbH.

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Krauth, MT., Alpermann, T., Bacher, U. et al. WT1 mutations are secondary events in AML, show varying frequencies and impact on prognosis between genetic subgroups. Leukemia 29, 660–667 (2015). https://doi.org/10.1038/leu.2014.243

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