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Oncogenes Fusion Genes and Tumor Suppressor Genes

FLT3 K663Q is a novel AML-associated oncogenic kinase: determination of biochemical properties and sensitivity to Sunitinib (SU11248)

Leukemia volume 20, pages 2008–2014 (2006)Cite this article

Abstract

Somatic mutations of FLT3 resulting in constitutive kinase activation are the most common acquired genomic abnormality found in acute myeloid leukemia (AML). The majority of these mutations are internal tandem duplications (ITD) of the juxtamembrane region (JM). In addition, a minority of cases of AML are associated with mutation of the FLT3 activation loop (AL), typically involving codons D835 and/or I836. We hypothesized that other novel mutations of FLT3 could also contribute to leukemogenesis. We genotyped 109 cases of AML and identified two novel gain-of-function mutations. The first mutation, N841 H, is similar to previously described mutations involving amino-acid substitutions of codon 841. The other novel mutation, FLT3 K663Q, is the first AML-associated gain-of-function mutation located outside the JM and AL domains. Of note, this mutation was potently inhibited by Sunitinib (SU11248), a previously described FLT3 kinase inhibitor. Sunitinib reduced the proliferation and induced apoptosis of transformed Ba/F3 cells expressing FLT3 K663Q. The potency of Sunitinib against FLT3 K663Q was similar to its potency against FLT3 ITD mutations. We conclude that FLT3 mutations in AML can involve novel regions of the TK1. Future studies are needed to define the incidence and prognostic significance of FLT3 mutations outside the well-established JM and AL regions.

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Acknowledgements

Flow cytometry support was provided by the Flow Cytometry Shared Resource of the OHSU Cancer Institute (P30 CA69533). This was supported in part by a Merit Review Grant from the Department of Veterans Affairs (MCH), the Doris Duke Charitable Foundation (MCH&KWHY), the Leukemia and Lymphoma Society (MCH), an NIH Cancer Biology Training Grant (JWT, Award number 5-T32-CA101690-03), the Deutsche Krebshilfe Foundation (MMS) and the fortüne-Program of the University of Tübingen (1490-0-0) (MMS). Several of the authors (A-MO, JMC) were employed by a company (SUGEN Inc.) whose product was studied in the present work.

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Authors and Affiliations

  1. Department of Pathology and Medicine, Oregon Health and Science University Cancer Institute and Portland Veterans Affairs Medical Center, Portland, OR, USA

    M M Schittenhelm, K W H Yee, J W Tyner, L McGreevey, A D Haley, A Town, D J Griffith, T Bainbridge, R M Braziel & M C Heinrich

  2. Department of Hematology, Oncology, Rheumatology, Immunology and Pneumology, University Medical Center, Eberhard-Karls-Universität Tübingen, Tübingen, Germany

    M M Schittenhelm

  3. Department of Preclinical Research and Exploratory Medicine, SUGEN Inc., South San Francisco, CA, USA

    A-M O'Farrell & J M Cherrington

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  1. M M Schittenhelm
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Correspondence to M C Heinrich.

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Schittenhelm, M., Yee, K., Tyner, J. et al. FLT3 K663Q is a novel AML-associated oncogenic kinase: determination of biochemical properties and sensitivity to Sunitinib (SU11248). Leukemia 20, 2008–2014 (2006). https://doi.org/10.1038/sj.leu.2404374

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