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 microM, 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.
MeSH terms
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Animals
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Antineoplastic Agents / therapeutic use*
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Benzoquinones
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Cell Line, Transformed / transplantation
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Cell Transformation, Neoplastic / genetics*
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / therapeutic use*
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Female
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Genistein / therapeutic use
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Humans
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Hydroquinones / therapeutic use
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Interleukin-3 / pharmacology
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Lactams, Macrocyclic
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Leukemia, Experimental / drug therapy*
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Mice
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Mice, Inbred C3H
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Transplantation
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Phosphorylation / drug effects
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Phthalimides / therapeutic use
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Protein Processing, Post-Translational / drug effects
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Quinones / therapeutic use
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / physiology*
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Rifabutin / analogs & derivatives
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Signal Transduction / drug effects
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Transfection
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Tyrphostins / therapeutic use
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fms-Like Tyrosine Kinase 3
Substances
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Antineoplastic Agents
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Benzoquinones
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Enzyme Inhibitors
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Hydroquinones
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Interleukin-3
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Lactams, Macrocyclic
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Neoplasm Proteins
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Phthalimides
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Proto-Oncogene Proteins
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Quinones
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Tyrphostins
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tyrphostin A9
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Rifabutin
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herbimycin
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Genistein
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FLT3 protein, human
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Flt3 protein, mouse
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Protein-Tyrosine Kinases
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Receptor Protein-Tyrosine Kinases
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fms-Like Tyrosine Kinase 3
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erbstatin
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4,5-dianilinophthalimide