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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1591-1598.
Prepublished online as a Blood First Edition Paper on October 25, 2005; DOI 10.1182/blood-2005-05-2123.
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Submitted May 26, 2005
Accepted October 6, 2005
BCR-ABL nuclear entrapment kills human CML cells: ex vivo study on 35 patients with the combination of Imatinib Mesylate and Leptomycin B
Alessandra ALOISI, Sandra DI GREGORIO, Fabio STAGNO, Patrizia GUGLIELMO, Francesca MANNINO, Maria Pia SORMANI, Paolo BRUZZI, Carlo GAMBACORTI-PASSERINI, Giuseppe SAGLIO, Salvatore VENUTA, Rosario GIUSTOLISI, Angelo MESSINA, and Paolo G VIGNERI*
Department of Biomedical Sciences, University of Catania, Catania, Italy
Department of Clinical Epidemiology, National Cancer Research Institute Genova, Genova, Italy
Department of Internal Medicine, University of Milano Bicocca, Milan, Italy
Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
Department of Clinical and Experimental Medicine, University of Catanzaro, Catanzaro, Italy
* Corresponding author; email: pvigneri{at}libero.it.
The BCR-ABL oncoprotein of Chronic Myelogenous Leukemia (CML) localizes to the cell cytoplasm where it activates proliferative and anti-apoptotic signaling pathways.
We previously reported that the combination of the ABL kinase inhibitor Imatinib Mesylate (IM) and the nuclear export inhibitor Leptomycin B (LMB) traps BCR-ABL inside the nucleus, triggering the death of the leukemic cells.
To evaluate the efficacy of the combination of IM and LMB on human cells we collected CD34-positive cells from 6 healthy donors and myeloid progenitors from 35 CML patients.
The sequential addition of IM and LMB generated the strongest reduction in the proliferative potential of the leukemic cells, with limited toxicity to normal myeloid precursors. Furthermore, nested RT-PCR analysis on colonies representative of each experimental condition demonstrated that the combination of IM and LMB was the most effective regimen in reducing the number of BCR-ABL-positive colonies. The efficacy of the two-drug association was independent of the clinical characteristics of the patients.
Our results indicate that strategies aimed at the nuclear entrapment of BCR-ABL efficiently kill human leukemic cells, suggesting that the clinical development of this approach could be of significant therapeutic value for newly-diagnosed and IM-resistant CML patients.
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