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Tyrosine Kinase Inhibitors

In vivo treatment of mutant FLT3-transformed murine leukemia with a tyrosine kinase inhibitor

Leukemia volume 14, pages 374–378 (2000)Cite this article

Abstract

Somatic mutation of the FLT3 gene, in which the juxtamembrane domain has an internal tandem duplication, is found in 20% of human acute myeloid leukemias and causes constitutive tyrosine phosphorylation of the products. In this study, we observed that the transfection of mutant FLT3 gene into an IL3-dependent murine cell line, 32D, abrogated the IL3-dependency. Subcutaneous injection of the transformed 32D cells caused leukemia in addition to subcutaneous tumors in C3H/HeJ mice. To develop a FLT3-targeted therapy, we examined tyrosine kinase inhibitors for in vitro growth suppression of the transformed 32D cells. A tyrosine kinase inhibitor, herbimycin A, remarkably inhibited the growth of the transformed 32D cells at 0.1 μM, at which concentration it was ineffective in parental 32D cells. Herbimycin A suppressed the constitutive tyrosine phosphorylation of the mutant FLT3 but not the phosphorylation of the ligand-stimulated wild-type FLT3. In mice transplanted with the transformed 32D cells, the administration of herbimycin A prolonged the latency of disease or completely prevented leukemia, depending on the number of cells inoculated and schedule of drug administration. These results suggest that mutant FLT3 is a promising target for tyrosine kinase inhibitors in the treatment of leukemia.

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Acknowledgements

We thank Chisato Kamiya, Yoko Kudo and Yoko Tagawa for their technical assistance, and Kirin Brewery Company Ltd for providing murine IL3.

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Authors and Affiliations

  1. Department of Infectious Diseases, Nagoya University School of Medicine, Nagoya, Japan

    M Zhao, H Kiyoi & T Naoe

  2. First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan

    Y Yamamoto, M Towatari & H Saito

  3. Department of Pathology, Nagoya University School of Medicine, Nagoya, Japan

    M Ito

  4. Kitasato Institute, Tokyo, Japan

    S Ômura

  5. Institute of Medical Science, University of Tokyo, Tokyo, Japan

    T Kitamura

  6. Second Department of Internal Medicine, Medical School, Nagoya City University, Nagoya, Japan

    R Ueda

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Zhao, M., Kiyoi, H., Yamamoto, Y. et al. In vivo treatment of mutant FLT3-transformed murine leukemia with a tyrosine kinase inhibitor. Leukemia 14, 374–378 (2000). https://doi.org/10.1038/sj.leu.2401680

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