title: 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.
abstract: 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.
authors: Dept. of Internal Medicine III, Technical University of Munich, Ismaningerstr. 22, 81675 Munich, Germany.
authors: Rama Krishna
authors: RK
authors: Kancha
authors: Nikolas
authors: N
authors: von Bubnoff
authors: Cornelius
authors: C
authors: Miething
authors: Christian
authors: C
authors: Peschel
authors: Katharina S
authors: KS
authors: Götze
authors: Justus
authors: J
authors: Duyster
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002892:Chromosomes, Human, Pair 22; D002899:Chromosomes, Human, Pair 9; D003114:Colony-Forming Units Assay; D004351:Drug Resistance / Q000502:physiology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl; D005784:Gene Amplification; D016313:Genes, abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D009154:Mutation; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D014178:Translocation, Genetic
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D005231:Fatty Acids, Unsaturated; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C038753:leptomycin B