A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations.
Internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 have been found in 20% to 30% of patients with acute myeloid leukemia (AML). These mutations constitutively activate the receptor and appear to be associated with a poor prognosis. Recent evidence that this constitutive activation is leukemogenic renders this receptor a potential target for specific therapy. In this study, dose-response cytotoxic assays were performed with AG1295, a tyrosine kinase inhibitor active against FLT3, on primary blasts from patients with AML. For each patient sample, the degree of cytotoxicity induced by AG1295 was compared to the response to cytosine arabinoside (Ara C) and correlated with the presence or absence of a FLT3/ITD mutation. AG1295 was specifically cytotoxic to AML blasts harboring FLT3/ITD mutations. The results suggest that these mutations contribute to the leukemic process and that the FLT3 receptor represents a therapeutic target in AML. (Blood. 2001;98:885-887)
Levis
M
M
Johns Hopkins University School of Medicine, Department of Oncology, Baltimore, MD 21231, USA.
Tse
K F
KF
Smith
B D
BD
Garrett
E
E
Small
D
D
D000208:Acute Disease; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D020080:Tandem Repeat Sequences / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3
C407689:6,7-dimethoxy-2-phenylquinoxaline; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D020032:Tyrphostins; C497970:FLT3 protein, human; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3