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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

, : 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 93(11): 1718-1722

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.


PMID: 18728023

DOI: 10.3324/haematol.13207

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