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

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    186 Scopus citations

    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
    Publication statusPublished - Sep 2005

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    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