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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. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 2005-05-2123v1 107/4/1591    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Aloisi, A. Articles by Vigneri, P. Search for Related Content PubMed PubMed Citation Articles by Aloisi, A. Articles by Vigneri, P. Related Collections Neoplasia Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA 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 Vigneri From the Department of Biomedical Sciences, University of Catania, Italy; Department of Clinical Epidemiology, the National Cancer Research Institute Genoa, Italy; Department of Internal Medicine, the University of Milano Bicocca, Italy; Department of Clinical and Biological Sciences, the University of Turin, Italy; and Department of Clinical and Experimental Medicine, the University of Catanzaro, Italy. The BCR-ABL oncoprotein of chronic myelogenous leukemia (CML) localizes to the cell cytoplasm, where it activates proliferative and antiapoptotic 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 patients with CML. 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 reverse transcriptase-polymerase chain reaction (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 2-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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. C. Mutka, W. Q. Yang, S. D. Dong, S. L. Ward, D. A. Craig, P. B.M.W.M. Timmermans, and S. Murli Identification of Nuclear Export Inhibitors with Potent Anticancer Activity In vivo Cancer Res., January 15, 2009; 69(2): 510 - 517. [Abstract] [Full Text] [PDF] M. Baccarani, G. Saglio, J. Goldman, A. Hochhaus, B. Simonsson, F. Appelbaum, J. Apperley, F. Cervantes, J. Cortes, M. Deininger, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet Blood, September 15, 2006; 108(6): 1809 - 1820. [Abstract] [Full Text] [PDF]

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