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The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth arrest and apoptosis in AML-derived cell lines expressing a constitutively activated FLT3.
- Source :
-
Blood [Blood] 2003 Feb 15; Vol. 101 (4), pp. 1494-504. Date of Electronic Publication: 2002 Oct 24. - Publication Year :
- 2003
-
Abstract
- Activating mutations of the protein tyrosine kinase (PTK) FLT3 can be found in approximately 30% of patients with acute myeloid leukemia (AML), thereby representing the most frequent single genetic alteration in AML. These mutations occur in the juxtamembrane (FLT3 length mutations; FLT3-LMs) and the second tyrosine kinase domain of FLT3-TKD and confer interleukin 3 (IL-3)-independent growth to Ba/F3 cells. In the mouse bone marrow transplantation model, FLT3-LMs induce a myeloproliferative syndrome stressing their transforming activity in vivo. In this study, we analyzed the pro-proliferative and antiapoptotic potential of FLT3 in FLT3-LM/TKD-mutation-transformed Ba/F3 cells and AML-derived cell lines. The PTK inhibitor SU5614 has inhibitory activity for FLT3 and selectively induces growth arrest, apoptosis, and cell cycle arrest in Ba/F3 and AML cell lines expressing a constitutively activated FLT3. In addition, the compound reverts the antiapoptotic and pro-proliferative activity of FLT3 ligand (FL) in FL-dependent cells. No cytotoxic activity of SU5614 was found in leukemic cell lines that express a nonactivated FLT3 or no FLT3 protein. At the biochemical level, SU5614 down-regulated the activity of the hyperphosphorylated FLT3 receptor and its downstream targets, signal transducer and activator of (STAT) 3, STAT5, and mitogen-activated protein kinase (MAPK), and the STAT5 target genes BCL-X(L) and p21. Our results show that SU5614 is a PTK inhibitor of FLT3 and has antiproliferative and proapoptotic activity in AML-derived cell lines that endogenously express an activated FLT3 receptor. The selective and potent cytotoxicity of FLT3 PTK inhibitors support a clinical strategy of targeting FLT3 as a new molecular treatment option for patients with FLT3-LM/TKD-mutation(+) AML.
- Subjects :
- Animals
Blotting, Western
Bone Marrow Transplantation
DNA-Binding Proteins antagonists & inhibitors
Flow Cytometry
Gene Expression
Green Fluorescent Proteins
Humans
Leukemia, Myeloid, Acute genetics
Luminescent Proteins genetics
Mice
Mitogen-Activated Protein Kinases
Mutagenesis
Mutation
Myeloproliferative Disorders genetics
Polymerase Chain Reaction
Protein-Tyrosine Kinases antagonists & inhibitors
Proto-Oncogene Proteins genetics
Receptor Protein-Tyrosine Kinases genetics
STAT5 Transcription Factor
Trans-Activators antagonists & inhibitors
Transfection
Tumor Cells, Cultured
fms-Like Tyrosine Kinase 3
Apoptosis drug effects
Cell Division drug effects
Enzyme Inhibitors pharmacology
Indoles pharmacology
Leukemia, Myeloid, Acute pathology
Milk Proteins
Proto-Oncogene Proteins antagonists & inhibitors
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 101
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 12406902
- Full Text :
- https://doi.org/10.1182/blood-2002-04-1045