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Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML.
Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML.
- Source :
-
Blood [Blood] 2004 Sep 15; Vol. 104 (6), pp. 1855-8. Date of Electronic Publication: 2004 Jun 03. - Publication Year :
- 2004
-
Abstract
- The FLT3 receptor is activated by juxtamembrane insertion mutations and by activation loop point mutations in patients with acute myeloid leukemia (AML). In a systematic tyrosine kinase gene exon resequencing study, 21 of 24 FLT3 exons were sequenced in samples from 53 patients with AML, 9 patients with acute lymphoblastic leukemia (ALL), and 3 patients with myelodysplasia samples. Three patients had novel point mutations at residue N841 that resulted in a change to isoleucine in 2 samples and to tyrosine in 1 sample. Introduction of FLT3-N841I cDNA into Ba/F3 cells led to interleukin-3 (IL-3)-independent proliferation, receptor phosphorylation, and constitutive activation of signal transducer and activator of transcription 5 (STAT5) and extracellular regulatory kinase (ERK), suggesting that the N841I mutation confers constitutive activity to the receptor. An FLT3 inhibitor (PKC412) inhibited the growth of Ba/F3-FLT3N841I cells (IC(50) 10 nM), but not of wild-type Ba/F3 cells cultured with IL-3. PKC412 also reduced tyrosine phosphorylation of the mutant receptor and inhibited STAT5 phosphorylation. Examination of the FLT3 autoinhibited structure showed that N841 is the key residue in a hydrogen-bonding network that likely stabilizes the activation loop. These results suggest that mutations at N841 represent a significant new activating mutation in patients with AML and that patients with such mutations may respond to small-molecule FLT3 inhibitors such as PKC412.
- Subjects :
- Adult
Aged
Aged, 80 and over
Cell Division drug effects
Enzyme Activation
Female
Humans
Hydrogen Bonding
Interleukin-3 pharmacology
Leukemia, Myeloid, Acute metabolism
Leukemia, Myeloid, Acute pathology
Male
Middle Aged
Models, Molecular
Phosphorylation
Protein Structure, Tertiary
Proto-Oncogene Proteins chemistry
Receptor Protein-Tyrosine Kinases chemistry
Signal Transduction
Staurosporine pharmacology
fms-Like Tyrosine Kinase 3
Leukemia, Myeloid, Acute enzymology
Leukemia, Myeloid, Acute genetics
Mutation genetics
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins metabolism
Receptor Protein-Tyrosine Kinases genetics
Receptor Protein-Tyrosine Kinases metabolism
Staurosporine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 104
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 15178581
- Full Text :
- https://doi.org/10.1182/blood-2004-02-0712