|
|
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.
 Previous Article | Next Article 
Submitted September 13, 2007
Accepted December 16, 2007
BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergises with tyrosine kinase inhibitors
Mhairi Copland, Francesca Pellicano, Linda Richmond, Elaine K Allan, Ashley Hamilton, Francis Y Lee, Roberto Weinmann, and Tessa L Holyoake*
Section of Experimental Haematology and Haemopoietic Stem Cells, Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Glasgow, United Kingdom
Department of Haematology, Glasgow Royal Infirmary, Glasgow, United Kingdom
Oncology Global Research, Bristol Myers Squibb Oncology, Princeton, NJ, United States
* Corresponding author; email: tlh1g{at}clinmed.gla.ac.uk.
Chronic myeloid leukemia (CML), a hematopoietic stem cell disorder, cannot be eradicated by conventional chemotherapy or the tyrosine kinase inhibitor (TKI) imatinib mesylate (IM). To target CML stem/progenitor cells we investigated BMS-214662, a cytotoxic farnesyltransferase inhibitor, previously reported to kill non-proliferating 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 <1% recovery of Philadelphia positive LTC-IC. 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 TKI and equally effective in cell lines harbouring wild-type versus 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:
|
|
|
|
 
F. Pellicano, M. Copland, H. G. Jorgensen, J. Mountford, B. Leber, and T. L. Holyoake
BMS-214662 induces mitochondrial apoptosis in chronic myeloid leukemia (CML) stem/progenitor cells, including CD34+38- cells, through activation of protein kinase C{beta}
Blood,
November 5, 2009;
114(19):
4186 - 4196.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
H. Konig, M. Copland, S. Chu, R. Jove, T. L. Holyoake, and R. Bhatia
Effects of Dasatinib on Src Kinase Activity and Downstream Intracellular Signaling in Primitive Chronic Myelogenous Leukemia Hematopoietic Cells
Cancer Res.,
December 1, 2008;
68(23):
9624 - 9633.
[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]
|
|
|
|
|
