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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2843-2853. Prepublished online as a Blood First Edition Paper on December 21, 2007; DOI 10.1182/blood-2007-09-112573. This Article Full Text Full Text (PDF) Supplemental Figure Erratum (v111,p4830) All Versions of this Article: blood-2007-09-112573v1 111/5/2843    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 Copland, M. Articles by Holyoake, T. L. Search for Related Content PubMed PubMed Citation Articles by Copland, M. Articles by Holyoake, T. L. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors Mhairi Copland1, Francesca Pellicano1, Linda Richmond2, Elaine K. Allan1, Ashley Hamilton1, Francis Y. Lee3, Roberto Weinmann3, and Tessa L. Holyoake1 1 Section of Experimental Haematology and Haemopoietic Stem Cells, Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Glasgow, United Kingdom; 2 Department of Haematology, Glasgow Royal Infirmary, Glasgow, United Kingdom; and 3 Bristol-Myers Squibb Oncology, Princeton, NJ Chronic myeloid leukemia (CML), a hematopoietic stem-cell disorder, cannot be eradicated by conventional chemotherapy or the tyrosine kinase inhibitor imatinib mesylate (IM). To target CML stem/progenitor cells, we investigated BMS-214662, a cytotoxic farnesyltransferase inhibitor, previously reported to kill nonproliferating tumor cells. IM or dasatinib alone reversibly arrested proliferation of CML stem/progenitor cells without inducing apoptosis. In contrast, BMS-214662, alone or in combination with IM or dasatinib, potently induced apoptosis of both proliferating and quiescent CML stem/progenitor cells with less than 1% recovery of Philadelphia-positive long-term culture-initiating cells. Normal stem/progenitor cells were relatively spared by BMS-214662, suggesting selectivity for leukemic stem/progenitor cells. The ability to induce selective apoptosis of leukemic stem/progenitor cells was unique to BMS-214662 and not seen with a structurally similar agent BMS-225975. BMS-214662 was cytotoxic against CML blast crisis stem/progenitor cells, particularly in combination with a tyrosine kinase inhibitor and equally effective in cell lines harboring wild-type vs mutant BCR-ABL, including the T315I mutation. This is the first report of an agent with activity in resistant and blast crisis CML that selectively kills CML stem/progenitor cells through apoptosis and offers potential for eradication of chronic phase CML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. S. M. Yong, K. Keyvanfar, N. Hensel, R. Eniafe, B. N. Savani, M. Berg, A. Lundqvist, S. Adams, E. M. Sloand, J. M. Goldman, et al. Primitive quiescent CD34+ cells in chronic myeloid leukemia are targeted by in vitro expanded natural killer cells, which are functionally enhanced by bortezomib Blood, January 22, 2009; 113(4): 875 - 882. [Abstract] [Full Text] [PDF] A. Quintas-Cardama and J. Cortes Therapeutic Options Against BCR-ABL1 T315I-Positive Chronic Myelogenous Leukemia Clin. Cancer Res., July 15, 2008; 14(14): 4392 - 4399. [Abstract] [Full Text] [PDF]

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