Medical Oncology

, Volume 27, Issue 3, pp 640–645 | Cite as

Incidence of FLT3 and nucleophosmin gene mutations in childhood acute myeloid leukemia: Serbian experience and the review of the literature

  • Nada KrstovskiEmail author
  • Natasa Tosic
  • Dragana Janic
  • Lidija Dokmanovic
  • Milos Kuzmanovic
  • Vesna Spasovski
  • Sonja Pavlovic
Original Paper


Mutations in the fms-like tyrosine kinase 3 (FLT3) gene (internal tandem duplication (ITD) and point mutation in the tyrosine kinase domain, FLT3/D835) as well as the nucleophosmin (NPM1) gene are the most common abnormalities in adult acute myeloid leukemia (AML). Their significance in pediatric AML is still unclear. In this study we evaluated the frequency of FLT3 and NPM1 mutations in childhood AML. We also examined clinical features and outcome of these patients. FLT3 and NPM1 mutations were analysed in 42 and 37 childhood AML patients, respectively, using polymerase chain reaction (PCR) and direct sequencing. FLT3 mutations were detected in 4/42 patients (9.5%). The frequencies of FLT3/ITD and FLT3/D835 were the same, 2/42 (4.7%). NMP1 mutations were found in 1/37 patients (2.7%). FLT3 gene mutations were correlated with induction failure. Here we report the results of the study of FLT3 and NPM1 gene mutations in childhood AML patients in Serbia. Low frequencies of these molecular markers point out that these abnormalities are rare in this cohort of patients. Comparative study of data on NPM1 mutations in childhood AML revealed that various NPM1 gene mutation types are associated with childhood AML. Our findings as well as previously reported data, contributes to a hypothesis of different biology and etiology of adult and childhood AML. More extensive studies of NPM1 and FLT3 mutations in childhood AML are needed to determine their biological and clinical importance.


FLT3 mutations NMP1 mutations Acute myeloid leukemia Children 



This study is supported by grant 143 051 from the Ministry of Science of Serbia.


  1. 1.
    Drexler HG. Expression of FLT3 receptor and response to FLT3 ligand by leukemic cell. Leukemia. 1996;10:588–9.PubMedGoogle Scholar
  2. 2.
    Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematological malignancies. Blood. 2001;97:2434–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, et al. The presence of FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98:1752–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Zwaan CM, Meshinchi S, Radich JP, Veerman AJ, Huismans DR, et al. FLT3 internal tandem mutations in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Blood. 2003;102:2387–94.CrossRefPubMedGoogle Scholar
  5. 5.
    Liang DC, Shih LY, Hung IJ, Yang CP, Chen SH, et al. FLT3-TKD mutation in childhood acute myeloid leukemia. Leukemia. 2003;17:883–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Colovic N, Tosic N, Aveic S, Djuric M, Milic N, et al. Importance of early detection and follow-up of FLT3 mutations in patients with acute myeloid leukemia. Ann Hematol. 2007;86:741–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Kang HJ, Hong SH, Kim IH, Park BK, Han KS, et al. Prognostic significance of FLT3 mutations in pediatric non-promyelocytic acute myeloid leukemia. Leuk Res. 2005;29:617–23.CrossRefPubMedGoogle Scholar
  8. 8.
    Cordell JL, Pulford KA, Bigerna B, Roncador G, Banham A, et al. Detection of normal and chimeric nucleophosmin in human cells. Blood. 1999;93:632–42.PubMedGoogle Scholar
  9. 9.
    Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, et al. Cytolasmatic nucleophosmin in acute myelogenous leukemia with normal karyotype. N Engl J Med. 2005;352:254–66.CrossRefPubMedGoogle Scholar
  10. 10.
    Falini B, Nicoletti I, Martelli MF, Mecucci C. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc + AML): biologic and clinical features. Blood. 2007;109:874–85.CrossRefPubMedGoogle Scholar
  11. 11.
    Cazzaniga G, Dell`Oro MG, Mecucci C, Giarin E, Masetti R, et al. Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype. Blood. 2005;106:1419–22.CrossRefPubMedGoogle Scholar
  12. 12.
    Kiyoi H, Naoe T, Yokota S, Nakao M, Minami S, et al. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia. 1997;11:1447–52.CrossRefPubMedGoogle Scholar
  13. 13.
    Falini B, Marteli MP, Bolli N, Bonasso R, Ghia E, et al. Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia. Blood. 2006;108:1999–2005.CrossRefPubMedGoogle Scholar
  14. 14.
    Schnittger S, Schoch C, Kern W, Mecucci C, Tschulik C, et al. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 2005;106:3733–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Arrigoni P, Berreta C, Silvestri D, Rossi V, Rizzari C, et al. FLT3 internal tandem duplication in childhood acute myeloid leukemia: association with hyperleukocytosis in acute promyelocytic leukemia. Br J Haematol. 2003;120:89–92.CrossRefPubMedGoogle Scholar
  16. 16.
    Iwai T, Yokota S, Nakao M, Okamoto T, Taniwaki M, et al. Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia. Leukemia. 1999;13:38–43.CrossRefPubMedGoogle Scholar
  17. 17.
    Whitman SP, Ruppert AS, Radmacher MD, Mrozek K, Paschka P, et al. Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favourable prognostic significance. Blood. 2008;111:1552–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Brown P, McIntyre E, Rau R, Meshinchi S, Lacayo N, et al. The incidence and clinical significance of nucleophosmin mutations in childhood AML. Blood. 2007;110:979–85.CrossRefPubMedGoogle Scholar
  19. 19.
    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;21:366–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Kondo M, Horibe K, Takahashi Y, Matsumoto K, Fukuda M, et al. Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia. Med Pediatr Oncol. 1999;33:525–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Meshinchi S, Woods WG, Stirewalt DL, Sweetser DA, Buckley JD, et al. Prevalence and prognostic significance of FLT3 internal tandem duplication in pediatric acute myeloid leukemia. Blood. 2001;97:89–94.CrossRefPubMedGoogle Scholar
  22. 22.
    Liang DC, Shih LY, Hung IJ, Yang CP, Chen SH, et al. Clinical relevance of internal tandem duplication of the FLT3 gene in childhood acute myeloid leukemia. Cancer. 2002;94:3292–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Meshinchi S, Alonzo TA, Stirewalt DL, Zwaan M, Zimmerman M, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood. 2006;108:3654–61.CrossRefPubMedGoogle Scholar
  24. 24.
    Xu F, Taki T, Yang HW, Hanada R, Hongo T, et al. Tandem duplication of the FLT3 gene is found in acute lymphoblastic leukemia as well as acute myeloid leukemia but not in myelodysplastic syndrome or juvenile chronic myelogenous leukemia in children. Br J Haematol. 1999;105:155–62.CrossRefPubMedGoogle Scholar
  25. 25.
    Thiede C, Koch S, Creutzig E, Steudel C, Illmer T, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006;107:4011–20.CrossRefPubMedGoogle Scholar
  26. 26.
    Mullighan CG, Kennedy A, Zhou X, Radtke I, Philips LA, et al. Pediatric acute myeloid leukemia with NPM1 mutations is characterised by a gene expression profile with dysregulated HOX gen expression distinct from MLL-rearranged leukemias. Leukemia. 2007;21:2000–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Chou WC, Tantg JL, Lin LI, Yao M, Tsay W, et al. Nucleophosmin mutations in de novo acute myeloid leukemia the age-dependent incidences and stability during disease evolution. Cancer Res. 2006;66:3310–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Shimada A, Taki T, Kubota C, Tawa A, Horibe K, 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.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Nada Krstovski
    • 1
    Email author
  • Natasa Tosic
    • 2
  • Dragana Janic
    • 1
  • Lidija Dokmanovic
    • 1
  • Milos Kuzmanovic
    • 3
  • Vesna Spasovski
    • 2
  • Sonja Pavlovic
    • 2
  1. 1.Department of Hematology/OncologyUniversity Children Hospital, Medical Faculty University of BelgradeBelgradeSerbia
  2. 2.Laboratory for Molecular HematologyInstitute of Molecular Genetics and Genetic EngineeringBelgradeSerbia
  3. 3.Department of HematologyMother and Child Healthcare Institute “Dr Vukan Cupic”BelgradeSerbia

Personalised recommendations