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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
4
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pubmed:dateCreated |
2003-1-31
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/FLT3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Flt3 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Green Fluorescent Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Indoles,
http://linkedlifedata.com/resource/pubmed/chemical/Luminescent Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Milk Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/STAT5 Transcription Factor,
http://linkedlifedata.com/resource/pubmed/chemical/SU 5614,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/fms-Like Tyrosine Kinase 3
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0006-4971
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
101
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1494-504
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:12406902-Animals,
pubmed-meshheading:12406902-Apoptosis,
pubmed-meshheading:12406902-Blotting, Western,
pubmed-meshheading:12406902-Bone Marrow Transplantation,
pubmed-meshheading:12406902-Cell Division,
pubmed-meshheading:12406902-DNA-Binding Proteins,
pubmed-meshheading:12406902-Enzyme Inhibitors,
pubmed-meshheading:12406902-Flow Cytometry,
pubmed-meshheading:12406902-Gene Expression,
pubmed-meshheading:12406902-Green Fluorescent Proteins,
pubmed-meshheading:12406902-Humans,
pubmed-meshheading:12406902-Indoles,
pubmed-meshheading:12406902-Leukemia, Myeloid, Acute,
pubmed-meshheading:12406902-Luminescent Proteins,
pubmed-meshheading:12406902-Mice,
pubmed-meshheading:12406902-Milk Proteins,
pubmed-meshheading:12406902-Mitogen-Activated Protein Kinases,
pubmed-meshheading:12406902-Mutagenesis,
pubmed-meshheading:12406902-Mutation,
pubmed-meshheading:12406902-Myeloproliferative Disorders,
pubmed-meshheading:12406902-Polymerase Chain Reaction,
pubmed-meshheading:12406902-Protein-Tyrosine Kinases,
pubmed-meshheading:12406902-Proto-Oncogene Proteins,
pubmed-meshheading:12406902-Receptor Protein-Tyrosine Kinases,
pubmed-meshheading:12406902-STAT5 Transcription Factor,
pubmed-meshheading:12406902-Trans-Activators,
pubmed-meshheading:12406902-Transfection,
pubmed-meshheading:12406902-Tumor Cells, Cultured,
pubmed-meshheading:12406902-fms-Like Tyrosine Kinase 3
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pubmed:year |
2003
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pubmed:articleTitle |
The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth arrest and apoptosis in AML-derived cell lines expressing a constitutively activated FLT3.
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pubmed:affiliation |
Department of Medicine III, University Hospital Grosshadern, Clinical Cooperative Group Leukemia, GSF National Research Center for Environment and Health, Munich, Germany. spiekermann@gsf.de
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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