Reference - Detail
| RRC ID | 41636 |
|---|---|
| Author | Minami Y, Kiyoi H, Yamamoto Y, Yamamoto K, Ueda R, Saito H, Naoe T. |
| Title | Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors. |
| Journal | Leukemia |
| Abstract |
An internal tandem duplication of the juxtamembrane (JM) domain of FLT3, a family of ligand-activated receptor tyrosine kinases, has been found in 20% of cases of acute myeloid leukemia (AML), and this mutation is correlated with leukocytosis and a poor prognosis. As a therapeutic approach, we previously reported that herbimycin A (HA) inhibited the growth of tandemly duplicated FLT3 (TDFLT3)-transformed cells (Leukemia 2000; 14: 374). Here, we have investigated the mechanism behind the cytotoxicity of HA, an ansamycin derivative which is now known to target Hsp90. The treatment with HA or another Hsp90 inhibitor, radicicol, induced selective apoptosis in TDFLT3-transformed 32D cells (TDFLT3/32D). The tyrosine-phosphorylation of TDFLT3 was inhibited by HA, whereas FLT3 ligand-induced phosphorylation of wild-type FLT3 (WtFLT3) was not. The downstream signal molecules MAPK, Akt and STAT5a were also dephosphorylated by HA in TDFLT3/32D. Immunoprecipitation analysis showed that TDFLT3 but not WtFLT3 formed a complex with Hsp90, and that the HA treatment dissociated TDFLT3 from the Hsp90 chaperone complex. These findings imply that targeting of Hsp90 will facilitate the development of anti-TDFLT3 therapy, and that Hsp90 is closely involved in the oncogenic activation of FLT3. |
| Volume | 16(8) |
| Pages | 1535-40 |
| Published | 2002-8-1 |
| DOI | 10.1038/sj.leu.2402558 |
| PMID | 12145695 |
| MeSH | Animals Apoptosis / drug effects* Benzoquinones Cell Transformation, Neoplastic / genetics DNA-Binding Proteins / metabolism HSP90 Heat-Shock Proteins / antagonists & inhibitors* HSP90 Heat-Shock Proteins / chemistry Interleukin-3 / pharmacology Lactams, Macrocyclic Lactones / pharmacology* MAP Kinase Signaling System / drug effects Macrolides Macromolecular Substances Mice Milk Proteins* Myeloid Cells / drug effects Neoplasm Proteins / chemistry Neoplasm Proteins / genetics Neoplasm Proteins / physiology* Phosphorylation Protein Folding Protein Interaction Mapping Protein Processing, Post-Translational / drug effects Protein Serine-Threonine Kinases* Proto-Oncogene Proteins / chemistry Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism Proto-Oncogene Proteins / physiology* Proto-Oncogene Proteins c-akt Quinones / pharmacology* Receptor Protein-Tyrosine Kinases / chemistry Receptor Protein-Tyrosine Kinases / genetics Receptor Protein-Tyrosine Kinases / physiology* Rifabutin / analogs & derivatives STAT5 Transcription Factor Tandem Repeat Sequences Trans-Activators / metabolism fms-Like Tyrosine Kinase 3 |
| IF | 8.665 |
| Times Cited | 82 |
| WOS Category | HEMATOLOGY ONCOLOGY |
| Resource | |
| Human and Animal Cells | 32D(RCB1145) |