BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90 Academic Article uri icon


MeSH Major

  • Antineoplastic Agents
  • Drug Resistance, Neoplasm
  • Fusion Proteins, bcr-abl
  • HSP90 Heat-Shock Proteins
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Piperazines
  • Point Mutation
  • Pyrimidines


  • Clinical resistance to imatinib mesylate is commonly observed in patients with advanced Philadelphia chromosome- positive (Ph(+)) leukemias. Acquired resistance is typically associated with reactivation of BCR-ABL due to kinase domain mutations or gene amplification, indicating that BCR-ABL remains a viable target for inhibition in these patients. Strategies for overcoming resistance can be envisioned through exploitation of other molecular features of the BCR-ABL protein, such as its dependence on the molecular chaperone heat shock protein 90 (Hsp90). To determine whether inhibition of Hsp90 could induce degradation of imatinib mesylate-resistant, mutant BCR-ABL proteins, hematopoietic cells expressing 2 mutant BCR-ABL proteins found in imatinib mesylate-resistant patients (T315I and E255K) were examined for sensitivity to geldanamycin and 17-allylaminogeldanamycin (17-AAG). Both compounds induced the degradation of wild-type and mutant BCR-ABL and inhibited cell growth, with a trend indicating more potent activity against mutant BCR-ABL proteins. These data support clinical investigations of 17-AAG in imatinib mesylate-resistant Ph(+) leukemias.

publication date

  • October 15, 2002



  • Academic Article



  • eng

Digital Object Identifier (DOI)

  • 10.1182/blood-2002-05-1361

PubMed ID

  • 12351420

Additional Document Info

start page

  • 3041

end page

  • 4


  • 100


  • 8