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rdf:type |
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lifeskim:mentions |
umls-concept:C0026882,
umls-concept:C0031727,
umls-concept:C0037083,
umls-concept:C0929370,
umls-concept:C1333568,
umls-concept:C1514562,
umls-concept:C1705241,
umls-concept:C1705242,
umls-concept:C1707455,
umls-concept:C1880389,
umls-concept:C1883204,
umls-concept:C1883221
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pubmed:issue |
1
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pubmed:dateCreated |
2005-6-21
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pubmed:abstractText |
Activating mutations of Flt3 are found in approximately one third of patients with acute myeloid leukemia (AML) and are an attractive drug target. Two classes of Flt3 mutations occur: internal tandem duplications (ITDs) in the juxtamembrane and point mutations in the tyrosine kinase domain (TKD). We and others have shown that Flt3-ITD induced aberrant signaling including strong activation of signal transducer and activator of transcription 5 (STAT5) and repression of CCAAT/estradiol-binding protein alpha (c/EBPalpha) and Pu.1. Here, we compared the signaling properties of Flt3-ITD versus Flt3-TKD in myeloid progenitor cells. We demonstrate that Flt3-TKD mutations induced autonomous growth of 32D cells in suspension cultures. However, in contrast to Flt3-ITD and similar to wild-type Flt3 (Flt3-WT), Flt3-TKD cannot support colony formation in semisolid media. Also, in contrast to Flt3-ITD, neither Flt3-WT nor Flt3-TKD induced activation or induction of STAT5 target genes. Flt3-TKD also failed to repress c/EBPalpha and Pu.1. No significant differences were observed in receptor autophosphorylation and the phosphorylation of Erk-1 and -2, Akt, and Shc. Importantly, TKD but not ITD mutations were a log power more sensitive toward the tyrosine kinase inhibitor protein kinase C 412 (PKC412) than Flt3-WT. In conclusion, Flt3-ITD and Flt3-TKD mutations display differences in their signaling properties that could have important implications for their transforming capacity and for the design of mutation-specific therapeutic approaches.
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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/FLT3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Milk Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/PKC412,
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/Staurosporine,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/fms-Like Tyrosine Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/protein kinase modulator
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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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 |
1
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pubmed:volume |
106
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
265-73
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:15769897-Acute Disease,
pubmed-meshheading:15769897-Animals,
pubmed-meshheading:15769897-Apoptosis,
pubmed-meshheading:15769897-Cell Line,
pubmed-meshheading:15769897-DNA-Binding Proteins,
pubmed-meshheading:15769897-Humans,
pubmed-meshheading:15769897-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:15769897-Leukemia, Myeloid,
pubmed-meshheading:15769897-Milk Proteins,
pubmed-meshheading:15769897-Muridae,
pubmed-meshheading:15769897-Mutagenesis, Site-Directed,
pubmed-meshheading:15769897-Myeloid Cells,
pubmed-meshheading:15769897-Phosphorylation,
pubmed-meshheading:15769897-Point Mutation,
pubmed-meshheading:15769897-Protein Structure, Tertiary,
pubmed-meshheading:15769897-Proto-Oncogene Proteins,
pubmed-meshheading:15769897-Receptor Protein-Tyrosine Kinases,
pubmed-meshheading:15769897-STAT5 Transcription Factor,
pubmed-meshheading:15769897-Signal Transduction,
pubmed-meshheading:15769897-Staurosporine,
pubmed-meshheading:15769897-Tandem Repeat Sequences,
pubmed-meshheading:15769897-Trans-Activators,
pubmed-meshheading:15769897-Transcription Factors,
pubmed-meshheading:15769897-fms-Like Tyrosine Kinase 3
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pubmed:year |
2005
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pubmed:articleTitle |
AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations.
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pubmed:affiliation |
Department of Medicine, Hematology/Oncology and Interdisciplinary Center for Clinical Research, University Münster, Germany.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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