Imatinib and leptomycin B are effective in overcoming imatinib-resistance due to Bcr-Abl amplification and clonal evolution but not due to Bcr-Abl kinase domain mutation

Haematologica. 2008 Nov;93(11):1718-22. doi: 10.3324/haematol.13207. Epub 2008 Aug 25.


Treatment with imatinib is very effective in Bcr-Abl positive leukemia. However, development of resistance to this drug is a common phenomenon in late stage disease. The Bcr-Abl protein localizes to the cytoplasm in transformed cells but can enter the nucleus upon treatment with imatinib. Using leptomycin B, a nuclear export blocker, it has been shown that reactivated nuclear Bcr-Abl kinase activity can induce cell death, thus presenting an interesting potential treatment option for imatinib resistant disease. Here we show that the combination of imatinib and leptomycin B effectively induces cell death in imatinib-resistant Ba/F3 cells which display Bcr-Abl amplification or signs of clonal evolution. However, no such synergism is observed in imatinib-resistant Ba/F3 cells carrying the T315I mutation of Bcr-Abl or those which have lost Bcr-Abl expression. Thus, a partial inhibition of Bcr-Abl by imatinib is required for this approach in agreement with the proposed mode of action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Benzamides
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chromosomes, Human, Pair 22
  • Chromosomes, Human, Pair 9
  • Colony-Forming Units Assay
  • Drug Resistance / physiology*
  • Fatty Acids, Unsaturated / pharmacology
  • Fusion Proteins, bcr-abl
  • Gene Amplification*
  • Genes, abl / genetics*
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Mutation
  • Philadelphia Chromosome
  • Piperazines / pharmacology*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Protein-Tyrosine Kinases / genetics*
  • Pyrimidines / pharmacology*
  • Translocation, Genetic


  • Antineoplastic Agents
  • Benzamides
  • Fatty Acids, Unsaturated
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • leptomycin B