Skip to main content

Advertisement

SpringerLink
Log in

WT1 mutation in pediatric patients with acute myeloid leukemia: a report from the Japanese Childhood AML Cooperative Study Group

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Mutations in Wilms tumor 1 (WT1) have been reported in 10–22 % of patients with cytogenetically normal acute myeloid leukemia (CN-AML), but the prognostic implications of these abnormalities have not been clarified in either adults or children. One hundred and fifty-seven pediatric AML patients were analyzed for WT1 mutations around hotspots at exons 7 and 9; however, amplification of the WT1 gene by the reverse transcriptase-polymerase chain reaction was not completed in four cases (2.5 %). Of the 153 evaluable patients, 10 patients (6.5 %) had a mutation in WT1. The incidence of WT1 mutations was significantly higher in CN-AML than in others (15.2 vs. 4.5 %, respectively, P = 0.03). Of the 10 WT1-mutated cases, eight (80 %) had mutations in other genes, including FLT3-ITD in two cases, FLT3-D835 mutation in two, KIT mutation in three, MLL-PTD in three, NRAS mutation in one, and KRAS mutation in two (in some cases, more than one additional gene was mutated). The incidences of KIT and FLT3-D835 mutations were significantly higher in patients with than in those without WT1 mutation. No significant differences were observed in the 3-year overall survival and disease-free survival; however, the presence of WT1 mutation was related to a poor prognosis in patients with CN-AML, excluding those with FLT3-ITD and those younger than 3 years.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Gibson BE, Wheatley K, Hann IM, Stevens RF, Webb D, Hills RK, et al. Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials. Leukemia. 2005;19:2130–8.

    Article  PubMed  CAS  Google Scholar 

  2. Lie SO, Abrahamsson J, Clausen N, Forestier E, Hasle H, Hovi L, et al. Long term results in children with AML: NOPHO-AML Study Group—report of three consecutive trials. Leukemia. 2005;19:2090–100.

    Article  PubMed  CAS  Google Scholar 

  3. Creutzig U, Zimmermann M, Lehrnbecher T, Graf N, Hermann J, Niemeyer CM, et al. Less toxicity by optimizing chemotherapy, but not by addition of granulocyte colony-stimulating factor in children and adolescents with acute myeloid leukemia: results of AML-BFM 98. J Clin Oncol. 2006;24:4499–506.

    Article  PubMed  CAS  Google Scholar 

  4. Lange BJ, Smith FO, Feusner J, Barnard DR, Dinndorf P, Feig S, et al. Outcomes in CCG-2961, a children’s oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children’s oncology group. Blood. 2008;111:1044–53.

    Article  PubMed  CAS  Google Scholar 

  5. Tsukimoto I, Tawa A, Horibe K, Tabuchi K, Kigasawa H, Tsuchida M, et al. Risk-stratified therapy and the intensive use of cytarabine improves the outcome in childhood acute myeloid leukemia: The AML99 trial from the Japanese Childhood AML Cooperative Study Group. J Clin Oncol. 2009;27:4007–13.

    Article  PubMed  CAS  Google Scholar 

  6. Rubnitz JE, Inaba H, Dahl G, Ribeiro RC, Bowman WP, Taub J, et al. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML 02 multicentre trial. Lancet Oncol. 2010;11:543–52.

    Article  PubMed  CAS  Google Scholar 

  7. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, et al. The importance of diagnostic cytogenetics on outcome of AML: analysis of 1612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood. 1998;92:2322–33.

    PubMed  CAS  Google Scholar 

  8. Mrózek 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;109:431–48.

    Article  PubMed  Google Scholar 

  9. 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;25:3337–43.

    Article  PubMed  CAS  Google Scholar 

  10. 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;60:509–20.

    Article  PubMed  CAS  Google Scholar 

  11. Yang L, Han Y, Suarez Saiz F, Minden MD. A tumor suppressor and oncogene: the WT1 story. Leukemia. 2007;21:868–76.

    PubMed  CAS  Google Scholar 

  12. 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;61:1257–69.

    Article  PubMed  CAS  Google Scholar 

  13. 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 

  14. 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;87:2878–84.

    PubMed  CAS  Google Scholar 

  15. 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;107:3303–12.

    Article  PubMed  CAS  Google Scholar 

  16. 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;26:4595–602.

    Article  PubMed  CAS  Google Scholar 

  17. 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;26:5429–35.

    Article  PubMed  CAS  Google Scholar 

  18. 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;113:4505–11.

    Article  PubMed  CAS  Google Scholar 

  19. Hollink IH, van den Heuvel-Eibrink MM, Zimmermann M, Balgobind BV, Arentsen-Peters ST, Alders M, et al. Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia. Blood. 2009;113:5951–60.

    Article  PubMed  CAS  Google Scholar 

  20. 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;21:550–1.

    Article  PubMed  CAS  Google Scholar 

  21. 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;116:702–10.

    Article  PubMed  CAS  Google Scholar 

  22. Staffas A, Kanduri M, Hovland R, Rosenquist R, Ommen HB, Abrahamsson J, et al. Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia. Blood. 2011;118:5905–13.

    Article  PubMed  CAS  Google Scholar 

  23. Shimada A, Taki T, Tabuchi K, Tawa A, Horibe K, Tsuchida M, et al. KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): A study of the Japanese Childhood AML Cooperative Study Group. Blood. 2006;107:1806–9.

    Article  PubMed  CAS  Google Scholar 

  24. Kobayashi R, Tawa A, Hanada R, Horibe K, Tsuchida M, Tsukimoto I. Extramedullary infiltration at diagnosis and prognosis in children with acute myeloid leukemia. Pediatr Blood Cancer. 2007;48:393–8.

    Article  PubMed  Google Scholar 

  25. Shimada A, Taki T, Tabuchi K, Taketani T, Hanada R, Tawa A, et al. Tandem duplications of MLL and FLT3 are correlated with poor prognoses in pediatric acute myeloid leukemia: a study of the Japanese Childhood AML Cooperative Study Group. Pediatr Blood Cancer. 2008;50:264–9.

    Article  PubMed  Google Scholar 

  26. Xu F, Taki T, Yang HW, Hanada R, Hongo T, Ohnishi H, et al. Tandem duplication of the FLT3 gene is found in acute lymphoblastic leukaemia as well as acute myeloid leukaemia but not in myelodysplastic syndrome or juvenile chronic myelogenous leukaemia in children. Br J Haematol. 1999;105:155–62.

    Article  PubMed  CAS  Google Scholar 

  27. Taketani T, Taki T, Sugita K, Furuichi Y, Ishii E, Hanada R, et al. FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood. 2004;103:1085–8.

    Article  PubMed  CAS  Google Scholar 

  28. Sano H, Shimada A, Taki T, Murata C, Park MJ, Sotomatsu M, et al. RAS mutations are frequent in FAB type M4 and M5 of acute myeloid leukemia, and related to late relapse: a study of the Japanese Childhood AML Cooperative Study Group. Int J Hematol. 2012;95:509–15.

    Article  PubMed  Google Scholar 

  29. Shimada A, Taki T, Koga D, Tabuchi K, Tawa A, Hanada R, et al. High WT1 mRNA expression after induction chemotherapy and FLT3-ITD have prognostic impact in pediatric acute myeloid leukemia: a study of the Japanese Childhood AML Cooperative Study Group. Int J Hematol. 2012;96:469–76.

    Article  PubMed  CAS  Google Scholar 

  30. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1957;53:457–81.

    Article  Google Scholar 

  31. Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994;264:436–40.

    Article  PubMed  CAS  Google Scholar 

  32. Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature. 1994;368:753–6.

    Article  PubMed  CAS  Google Scholar 

  33. Okamoto A, Demetrick DJ, Spillare EA, Hagiwara K, Hussain SP, Bennett WP, et al. Mutations and altered expression of p16INK4 in human cancer. Proc Natl Acad Sci USA. 1994;91:11045–9.

    Article  PubMed  CAS  Google Scholar 

  34. Renneville A, Roumier C, Biggio V, Nibourel O, Boissel N, Fenaux P, et al. Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia. 2008;22:915–31.

    Article  PubMed  CAS  Google Scholar 

  35. Willasch AM, Gruhn B, Coliva T, Kalinova M, Schneider G, Kreyenberg H, et al. Standardization of WT1 mRNA quantitation for minimal residual disease monitoring in childhood AML and implications of WT1 gene mutations: a European multicenter study. Leukemia. 2009;23:1472–9.

    Article  PubMed  CAS  Google Scholar 

  36. Østergaard 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  PubMed  Google Scholar 

  37. Noronha SA, Farrar JE, Alonzo TA, Gerbing RB, Lacayo NJ, Dahl GV, et al. WT1 expression at diagnosis does not predict survival in pediatric AML: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2009;53:1136–9.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant for Cancer Research and a grant for Research on Children and Families from the Ministry of Health, Labor, and Welfare of Japan, a Grant-in-Aid for Scientific Research (B, C) and Exploratory Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by a Research grant for Gunma Prefectural Hospitals.

Conflict of interest

There is no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Hematology/Oncology, Gunma Children’s Medical Center, 779 Shimohakoda, Hokkitsu, Shibukawa, Gunma, 377-8577, Japan

    Hirozumi Sano, Akira Shimada, Chisato Murata, Myoung-ja Park, Kentaro Ohki, Manabu Sotomatsu & Yasuhide Hayashi

  2. Department of Pediatrics/Pediatric Hematology & Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Kita-ku, Okayama, 700-8558, Japan

    Akira Shimada

  3. Department of Hematology, Kanagawa Children’s Medical Center, 2-138-4 Mutsugawa, Minami-ku, Yokohama, Kanagawa, 232-8555, Japan

    Ken Tabuchi

  4. Department of Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Tomohiko Taki

  5. Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, 53 Shougoin, Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan

    Souichi Adachi

  6. Department of Pediatrics, National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka, 540-0006, Japan

    Akio Tawa

  7. Department of Pediatrics, Sapporo Hokuyu Hospital, 6-6 Higashi-Sapporo, Shiroishi-ku, Sapporo, 003-0006, Japan

    Hirozumi Sano & Ryoji Kobayashi

  8. Clinical Research Center, National Hospital Organization Nagoya Medical Center, 4-1-1 Sannomaru, Naka-ku, Nagoya, Aichi, 460-0001, Japan

    Keizo Horibe

  9. Department of Pediatrics, Ibaraki Children’s Hospital, 3-3-1 Futabadai, Mito, Ibaraki, 311-4145, Japan

    Masahiro Tsuchida

  10. Division of Hematology/Oncology, Saitama Children’s Medical Center, 2100 Oaza Magome, Iwatsuki-ku, Saitama, 339-8551, Japan

    Ryoji Hanada

  11. First Department of Pediatrics, Toho University School of Medicine, 6-11-1, Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan

    Ichiro Tsukimoto

Authors
  1. Hirozumi Sano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akira Shimada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ken Tabuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomohiko Taki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chisato Murata
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Myoung-ja Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kentaro Ohki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Manabu Sotomatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Souichi Adachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Akio Tawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ryoji Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Keizo Horibe
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Masahiro Tsuchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ryoji Hanada
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ichiro Tsukimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yasuhide Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasuhide Hayashi.

Appendix

Appendix

Committee members of the Japanese Childhood AML Cooperative Study Group who contributed data to this study include Akira Morimoto, Department of Pediatrics, Kyoto Prefectural University of Medicine; Hiromasa Yabe, Department of Pediatrics, Tokai University School of Medicine; Kazuko Hamamoto, Department of Pediatrics, Hiroshima Red Cross Hospital; Shigeru Tsuchiya, Department of Pediatric Oncology, Institute of Development, Aging and Cancer, Tohoku University; Yuichi Akiyama, Department of Pediatrics, National Hospital Organization Kyoto Medical Center; Hisato Kigasawa, Department of Hematology, Kanagawa Children’s Medical Center; Akira Ohara, First Department of Pediatrics, Toho University School of Medicine; Hideki Nakayama, Department of Pediatrics, Hamanomachi Hospital; Kazuko Kudo, Department of Pediatrics, Nagoya University Graduate School of Medicine; and Masue Imaizumi, Department of Hematology and Oncology, Miyagi Children’s Hospital.

About this article

Cite this article

Sano, H., Shimada, A., Tabuchi, K. et al. WT1 mutation in pediatric patients with acute myeloid leukemia: a report from the Japanese Childhood AML Cooperative Study Group. Int J Hematol 98, 437–445 (2013). https://doi.org/10.1007/s12185-013-1409-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-013-1409-6

Keywords

Search

Navigation