Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia

B. F. Goemans, Ch M. Zwaan, M. Miller, M. Zimmermann, A. Harlow, S. Meshinchi, A. H. Loonen, K. Hählen, D. Reinhardt, U. Creutzig, G. J L Kaspers, Michael Heinrich

    Research output: Contribution to journalArticle

    182 Citations (Scopus)

    Abstract

    Activating mutations in RAS and receptor tyrosine kinases such as KIT and FLT3 are hypothesized to cooperate with chimeric transcription factors in the pathogenesis of acute myeloid leukemia (AML). To test this hypothesis, we genotyped 150 pediatric AML samples for mutations in KIT (exons 8, 17), NRAS and KRAS (exons 1, 2) and FLT3/ITD. This is the largest cohort of pediatric AML patients reported thus far screened for all four mutations. Of the children with AML, 40% had a mutation in KIT (11.3%), RAS (18%) or FLT3/ITD (11.1%), and 70% of cases of core-binding factor (CBF) leukemia were associated with a mutation of KIT or RAS. Mutations in RAS or FLT3/ITD were frequently found in association with a normal karyotype. Patients with a FLT3/ITD mutation had a significantly worse clinical outcome. However, the presence of a KIT or RAS mutation did not significantly influence clinical outcome. We demonstrate that KIT exon 8 mutations result in constitutive ligand-independent kinase activation that can be inhibited by clinically relevant concentrations of imatinib. Our results demonstrate that abnormalities of signal transduction pathways are frequent in pediatric AML. Future clinical studies are needed to determine whether selective targeting of these abnormalities will improve treatment results.

    Original languageEnglish (US)
    Pages (from-to)1536-1542
    Number of pages7
    JournalLeukemia
    Volume19
    Issue number9
    DOIs
    StatePublished - Sep 2005

    Fingerprint

    Core Binding Factors
    Acute Myeloid Leukemia
    Pediatrics
    Mutation
    Exons
    Receptor Protein-Tyrosine Kinases
    Karyotype
    Signal Transduction
    Leukemia
    Transcription Factors
    Phosphotransferases

    Keywords

    • AML
    • CBF
    • Exon 8
    • KIT
    • Pediatric
    • RAS

    ASJC Scopus subject areas

    • Hematology
    • Cancer Research

    Cite this

    Goemans, B. F., Zwaan, C. M., Miller, M., Zimmermann, M., Harlow, A., Meshinchi, S., ... Heinrich, M. (2005). Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia, 19(9), 1536-1542. https://doi.org/10.1038/sj.leu.2403870

    Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. / Goemans, B. F.; Zwaan, Ch M.; Miller, M.; Zimmermann, M.; Harlow, A.; Meshinchi, S.; Loonen, A. H.; Hählen, K.; Reinhardt, D.; Creutzig, U.; Kaspers, G. J L; Heinrich, Michael.

    In: Leukemia, Vol. 19, No. 9, 09.2005, p. 1536-1542.

    Research output: Contribution to journalArticle

    Goemans, BF, Zwaan, CM, Miller, M, Zimmermann, M, Harlow, A, Meshinchi, S, Loonen, AH, Hählen, K, Reinhardt, D, Creutzig, U, Kaspers, GJL & Heinrich, M 2005, 'Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia', Leukemia, vol. 19, no. 9, pp. 1536-1542. https://doi.org/10.1038/sj.leu.2403870
    Goemans BF, Zwaan CM, Miller M, Zimmermann M, Harlow A, Meshinchi S et al. Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia. 2005 Sep;19(9):1536-1542. https://doi.org/10.1038/sj.leu.2403870
    Goemans, B. F. ; Zwaan, Ch M. ; Miller, M. ; Zimmermann, M. ; Harlow, A. ; Meshinchi, S. ; Loonen, A. H. ; Hählen, K. ; Reinhardt, D. ; Creutzig, U. ; Kaspers, G. J L ; Heinrich, Michael. / Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. In: Leukemia. 2005 ; Vol. 19, No. 9. pp. 1536-1542.
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    AU - Meshinchi, S.

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