Copland, M., Pellicano, F., Richmond, L., Allan, E. K., Hamilton, A., Lee, F. Y., Weinmann, R. and Holyoake, T. L. (2008) BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors. Blood, 111(5), pp. 2843-2853. (doi: 10.1182/blood-2007-09-112573)
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Publisher's URL: http://dx.doi.org/10.1182/blood-2007-09-112573
Abstract
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 CIVIL 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 T315l 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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Hamilton, Ms Ashley and Pellicano, Dr Francesca and Holyoake, Professor Tessa and Allan, Mrs Elaine and Copland, Professor Mhairi |
| Authors: | Copland, M., Pellicano, F., Richmond, L., Allan, E. K., Hamilton, A., Lee, F. Y., Weinmann, R., and Holyoake, T. L. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Blood |
| Publisher: | American Society of Hematology |
| ISSN: | 0006-4971 |
| ISSN (Online): | 1528-0020 |
| Published Online: | 21 December 2007 |
| Related URLs: |
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