In vivo treatment of mutant FLT3-transformed murine leukemia with a tyrosine kinase inhibitor.
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.
Zhao
M
M
Department of Infectious Diseases, Nagoya University School of Medicine, Japan.
Kiyoi
H
H
Yamamoto
Y
Y
Ito
M
M
Towatari
M
M
Omura
S
S
Kitamura
T
T
Ueda
R
R
Saito
H
H
Naoe
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016227:Benzoquinones; D002461:Cell Line, Transformed / Q000637:transplantation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D019833:Genistein / Q000627:therapeutic use; D006801:Humans; D006873:Hydroquinones / Q000627:therapeutic use; D007377:Interleukin-3 / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D008809:Mice, Inbred C3H; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D010797:Phthalimides / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011809:Quinones / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D020032:Tyrphostins / Q000627:therapeutic use; D051941:fms-Like Tyrosine Kinase 3
D000970:Antineoplastic Agents; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D006873:Hydroquinones; D007377:Interleukin-3; D047029:Lactams, Macrocyclic; D009363:Neoplasm Proteins; D010797:Phthalimides; D011518:Proto-Oncogene Proteins; D011809:Quinones; D020032:Tyrphostins; C406122:tyrphostin A9; D017828:Rifabutin; C020754:herbimycin; D019833:Genistein; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; C048212:erbstatin; C098874:4,5-dianilinophthalimide