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FLT3-ITD-TKD dual mutants associated with AML confer resistance to FLT3 PTK inhibitors and cytotoxic agents by overexpression of Bcl-x(L).
- Source :
-
Blood [Blood] 2005 May 01; Vol. 105 (9), pp. 3679-85. Date of Electronic Publication: 2004 Dec 30. - Publication Year :
- 2005
-
Abstract
- FLT3 (fms-like tyrosine kinase 3) is constitutively activated in about 30% of patients with acute myeloid leukemia (AML) and represents a disease-specific molecular marker. Although FLT3-LM (length mutation) and TKD (tyrosine kinase domain) mutations have been considered to be mutually exclusive, 1% to 2% of patients carry both mutations. However, the functional and clinical significance of this observation is unclear. We demonstrate that FLT3-ITD-TKD dual mutants induce drug resistance toward PTK inhibitors and cytotoxic agents in in vitro model systems. As molecular mechanisms of resistance, we found that FLT3-ITD-TKD mutants cause hyperactivation of STAT5 (signal transducer and activator of transcription-5), leading to upregulation of Bcl-x(L) and RAD51 and arrest in the G(2)M phase of the cell cycle. Overexpression of Bcl-x(L) was identified as the critical mediator of drug resistance and recapitulates the PTK inhibitor and daunorubicin-resistant phenotype in FLT3-ITD cells. The combination of rapamycin, a selective mTOR inhibitor, and FLT3 PTK inhibitors restored the drug sensitivity in FLT3 dual mutant-expressing cells. Our data provide the molecular basis for understanding clinical FLT3 PTK inhibitor resistance and point to therapeutical strategies to overcome drug resistance in patients with AML.
- Subjects :
- Acute Disease
Animals
Cell Line
DNA-Binding Proteins drug effects
DNA-Binding Proteins genetics
Enzyme Inhibitors pharmacology
Humans
Mice
Milk Proteins drug effects
Protein-Tyrosine Kinases genetics
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins c-bcl-2 genetics
Rad51 Recombinase
Receptor Protein-Tyrosine Kinases genetics
Recombinant Fusion Proteins genetics
STAT5 Transcription Factor
Trans-Activators drug effects
Transfection
Up-Regulation drug effects
bcl-X Protein
fms-Like Tyrosine Kinase 3
Drug Resistance, Neoplasm drug effects
Leukemia, Myeloid drug therapy
Point Mutation
Protein-Tyrosine Kinases antagonists & inhibitors
Proto-Oncogene Proteins antagonists & inhibitors
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Recombinant Fusion Proteins pharmacology
Tandem Repeat Sequences
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 105
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 15626738
- Full Text :
- https://doi.org/10.1182/blood-2004-06-2459