Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors

Leukemia. 2002 Aug;16(8):1535-40. doi: 10.1038/sj.leu.2402558.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Benzoquinones
  • DNA-Binding Proteins
  • HSP90 Heat-Shock Proteins
  • Interleukin-3
  • Lactams, Macrocyclic
  • Lactones
  • Macrolides
  • Macromolecular Substances
  • Milk Proteins
  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • Quinones
  • STAT5 Transcription Factor
  • Stat5a protein, mouse
  • Trans-Activators
  • Rifabutin
  • herbimycin
  • Flt3 protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • fms-Like Tyrosine Kinase 3
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • monorden