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 Article
  • Published:

Acute Leukemias

Favorable prognostic impact of NPM1 gene mutations in childhood acute myeloid leukemia, with emphasis on cytogenetically normal AML

Leukemia volume 23, pages 262–270 (2009)Cite this article

Abstract

Nucleophosmin (NPM1) mutations occur frequently in adult cytogenetically normal acute myeloid leukemia (CN-AML) and confer favorable outcome. We investigated the frequency and prognostic significance of NPM1 mutations in childhood AML (n=298), specifically focusing on the CN-AML subgroup (n=100). Mutations were found in 8.4%, and clustered significantly in the CN-AML subgroup (22%). No mutations were found in patients below the age of 3 years; in CN-AML, there was an increasing incidence above this age. In the overall group, NPM1 mutations conferred an independent favorable prognostic impact on event-free survival (5-year pEFS 66 vs 39%; P=0.02), which did not translate into a significantly better overall survival (5-year pOS 68 vs 56%; P=0.30). However, when the favorable cytogenetic subgroups [inv(16) and t(8;21)] were excluded from the NPM1 wild-type group, the difference in pOS was borderline statistically significant (68 vs 45%; P=0.07). In the CN-AML cohort, NPM1 mutations were an independent prognostic factor on pEFS (80 vs 39%; P=0.01), and pOS (85 vs 60%; P=0.06), which was not influenced by FLT3/ITD. However, in NPM1 wild-type CN-AML, FLT3/ITD-positive patients had a significantly worse outcome (pEFS 48 vs 18%; P<0.001). We conclude that NPM1 mutations confer a favorable prognosis in childhood AML and in CN-AML in particular.

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Borer RA, Lehner CF, Eppenberger HM, Nigg EA . Major nucleolar proteins shuttle between nucleus and cytoplasm. Cell 1989; 56: 379–390.

    Article  CAS  Google Scholar 

  2. Cordell JL, Pulford KA, Bigerna B, Roncador G, Banham A, Colombo E et al. Detection of normal and chimeric nucleophosmin in human cells. Blood 1999; 93: 632–642.

    CAS  Google Scholar 

  3. Colombo E, Marine JC, Danovi D, Falini B, Pelicci PG . Nucleophosmin regulates the stability and transcriptional activity of p53. Nat Cell Biol. 2002; 4: 529–533.

    Article  CAS  Google Scholar 

  4. Brady SN, Yu Y, Maggi Jr LB, Weber JD . ARF impedes NPM/B23 shuttling in an Mdm2-sensitive tumor suppressor pathway. Mol Cell Biol 2004; 24: 9327–9338.

    Article  CAS  Google Scholar 

  5. Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005; 352: 254–266.

    Article  CAS  Google Scholar 

  6. Falini B, Bolli N, Shan J, Martelli MP, Liso A, Pucciarini A et al. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML. Blood 2006; 107: 4514–4523.

    Article  CAS  Google Scholar 

  7. Mariano AR, Colombo E, Luzi L, Martinelli P, Volorio S, Bernard L et al. Cytoplasmic localization of NPM in myeloid leukemias is dictated by gain-of-function mutations that create a functional nuclear export signal. Oncogene 2006; 25: 4376–4380.

    Article  CAS  Google Scholar 

  8. Thiede C, Koch S, Creutzig E, Steudel C, Illmer T, Schaich M et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 2006; 107: 4011–4020.

    Article  CAS  Google Scholar 

  9. Verhaak RG, Goudswaard CS, van Putten W, Bijl MA, Sanders MA, Hugens W et al. Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood 2005; 106: 3747–3754.

    Article  CAS  Google Scholar 

  10. Chou WC, Tang JL, Lin LI, Yao M, Tsay W, Chen CY et al. Nucleophosmin mutations in de novo acute myeloid leukemia: the age-dependent incidences and the stability during disease evolution. Cancer research 2006; 66: 3310–3316.

    Article  CAS  Google Scholar 

  11. Suzuki T, Kiyoi H, Ozeki K, Tomita A, Yamaji S, Suzuki R et al. Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood 2005; 106: 2854–2861.

    Article  CAS  Google Scholar 

  12. 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  Google Scholar 

  13. Boissel N, Renneville A, Biggio V, Philippe N, Thomas X, Cayuela JM et al. Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood 2005; 106: 3618–3620.

    Article  CAS  Google Scholar 

  14. Dohner K, Schlenk RF, Habdank M, Scholl C, Rucker FG, Corbacioglu A et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 2005; 106: 3740–3746.

    Article  Google Scholar 

  15. 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  Google Scholar 

  16. Pui CH, Schrappe M, Ribeiro RC, Niemeyer CM . Childhood and adolescent lymphoid and myeloid leukemia. Hematology Am Soc Hematol Educ Program 2004, 118–145.

    Article  Google Scholar 

  17. Cazzaniga G, Dell′Oro MG, Mecucci C, Giarin E, Masetti R, Rossi V et al. Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype. Blood 2005; 106: 1419–1422.

    Article  CAS  Google Scholar 

  18. Brown P, McIntyre E, Rau R, Meshinchi S, Lacayo N, Dahl G et al. The incidence and clinical significance of nucleophosmin mutations in childhood AML. Blood 2007; 110: 979–985.

    Article  CAS  Google Scholar 

  19. Shimada A, Taki T, Kubota C, Tawa A, Horibe K, Tsuchida M et al. No nucleophosmin mutations in pediatric acute myeloid leukemia with normal karyotype: a study of the Japanese Childhood AML Cooperative Study Group. Leukemia 2007; 21: 1307.

    Article  CAS  Google Scholar 

  20. Thiede C, Creutzig E, Reinhardt D, Ehninger G, Creutzig U . Different types of NPM1 mutations in children and adults: evidence for an effect of patient age on the prevalence of the TCTG-tandem duplication in NPM1-exon 12. Leukemia 2007; 21: 366–367.

    Article  CAS  Google Scholar 

  21. Kaspers GJ, Veerman AJ, Pieters R, Broekema GJ, Huismans DR, Kazemier KM et al. Mononuclear cells contaminating acute lymphoblastic leukaemic samples tested for cellular drug resistance using the methyl-thiazol-tetrazolium assay. Br J Cancer 1994; 70: 1047–1052.

    Article  CAS  Google Scholar 

  22. Kardos G, Zwaan CM, Kaspers GJ, de-Graaf SS, de Bont ES, Postma A et al. Treatment strategy and results in children treated on three Dutch Childhood Oncology Group acute myeloid leukemia trials. Leukemia 2005; 19: 2063–2071.

    Article  CAS  Google Scholar 

  23. Creutzig U, Zimmermann M, Ritter J, Reinhardt D, Hermann J, Henze G et al. Treatment strategies and long-term results in paediatric patients treated in four consecutive AML-BFM trials. Leukemia 2005; 19: 2030–2042.

    Article  CAS  Google Scholar 

  24. 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: 2130–2138.

    Article  CAS  Google Scholar 

  25. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326–4335.

    Article  CAS  Google Scholar 

  26. Cloos J, Goemans BF, Hess CJ, van Oostveen JW, Waisfisz Q, Corthals S et al. Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia 2006; 20: 1217–1220.

    Article  CAS  Google Scholar 

  27. Stam RW, den Boer ML, Schneider P, Nollau P, Horstmann M, Beverloo HB et al. Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia. Blood 2005; 106: 2484–2490.

    Article  CAS  Google Scholar 

  28. Falini B, Nicoletti I, Martelli MF, Mecucci C . Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood 2007; 109: 874–885.

    Article  CAS  Google Scholar 

  29. Biondi A, Rovelli A, Cantu-Rajnoldi A, Fenu S, Basso G, Luciano A et al. Acute promyelocytic leukemia in children: experience of the Italian Pediatric Hematology and Oncology Group (AIEOP). Leukemia 1994; 8 (Suppl 2): S66–S70.

    PubMed  Google Scholar 

  30. Goemans BF, Zwaan CM, Martinelli S, Harrell P, de Lange D, Carta C et al. Differences in the prevalence of PTPN11 mutations in FAB M5 paediatric acute myeloid leukaemia. Br J haematol 2005; 130: 801–803.

    Article  CAS  Google Scholar 

  31. Zwaan CM, Meshinchi S, Radich JP, Veerman AJ, Huismans DR, Munske L et al. FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Blood 2003; 102: 2387–2394.

    Article  CAS  Google Scholar 

  32. Cimino G, Rapanotti MC, Elia L, Biondi A, Fizzotti M, Testi AM et al. ALL-1 gene rearrangements in acute myeloid leukemia: association with M4-M5 French-American-British classification subtypes and young age. Cancer research 1995; 55: 1625–1628.

    CAS  PubMed  Google Scholar 

  33. Brown P, McIntyre E, Rau R, Alonzo TA, Gerbing R, Meshinchi S et al. Incidence and clinical significance of nucleophosmin mutations in childhood AML: a Childrens Oncology Group Study (abstract). Blood 2006; 108: 69a (abstract 221).

  34. Kaspers GJ, Zimmermann M, Reinhardt D, Tamminga R, Gibson B, Armendariz HM et al. Prognostic significance of early treatment response in pediatric relapsed acute myeloid leukemia: results from the International Study Relapsed AML 2001/01 (abstract). Blood 2007; 110: 546a (abstract 1843).

  35. Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 2008; 111: 2776–2784.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

These analyses were supported in part by the BMBF (Grant No. 03WKBH2H) to CT. DR was funded by the Deutsche Krebshilfe, and IHIMH by the KOCR foundation and EUR Trustfonds.

Author information

Authors and Affiliations

  1. Department of Pediatric Oncology and Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands

    I H I M Hollink, C M Zwaan, T C J M Arentsen-Peters, R Pieters & M M van den Heuvel-Eibrink

  2. Department of Pediatric Oncology/Hematology, AML-BFM Study Group, Medical High School, Hannover, Germany

    M Zimmermann & D Reinhardt

  3. Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands

    J Cloos & G J L Kaspers

  4. Department of Pediatric Hematology/Oncology, University Medical Center Nijmegen, Nijmegen, The Netherlands

    S S N de Graaf

  5. Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands

    S S N de Graaf

  6. Oncogenetic Laboratory, Children's University Hospital, Gießen, Germany

    J Harbott

  7. AML-BFM Study Group, University Children's Hospital, Münster, Germany

    U Creutzig

  8. Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der Technischen Universität, Dresden, Germany

    C Thiede

Authors
  1. C M Zwaan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Zimmermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T C J M Arentsen-Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Pieters
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Cloos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G J L Kaspers
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S S N de Graaf
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Harbott
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. U Creutzig
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D Reinhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M M van den Heuvel-Eibrink
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. C Thiede
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C M Zwaan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hollink, I., Zwaan, C., Zimmermann, M. et al. Favorable prognostic impact of NPM1 gene mutations in childhood acute myeloid leukemia, with emphasis on cytogenetically normal AML. Leukemia 23, 262–270 (2009). https://doi.org/10.1038/leu.2008.313

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.313

Keywords

This article is cited by

Search

Advanced search

Quick links