Abstract
The leukemic stem cells in patients with chronic myeloid leukemia (CML) are well known to be clinically resistant to conventional chemotherapy and may also be relatively resistant to BCR-ABL-targeted drugs. Here we show that the lesser effect of imatinib mesylate (IM) on the 3-week output of cells produced in vitro from lin−CD34+CD38− CML (stem) cells compared with cultures initiated with the CD38+ subset of lin−CD34+ cells is markedly enhanced (>10-fold) when conditions of reduced growth factor stimulation are used. Quantitative analysis of genes expressed in these different CML subsets revealed a differentiation-associated decrease in IL-3 and G-CSF transcripts, a much more profound decrease in expression of BCR-ABL than predicted by changes in BCR expression, decreasing expression of ABCB1/MDR and ABCG2 and increasing expression of OCT1. p210BCR-ABL and kinase activity were also higher in the lin−CD34+CD38− cells and formal evidence that increasing BCR-ABL expression decreases IM sensitivity was obtained from experiments with a cell line model. Nevertheless, within the entire CD34+ subset of CML cells, BCR-ABL expression was not strongly affected by changes in cell cycle status. Taken together, these results provide the first evidence of multiple mechanisms of innate IM resistance in primitive and quiescent CML cells.
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Acknowledgements
We thank Drs M Beran (MD Anderson Cancer Center, Houston, TX, USA), M Caligiuri (Ohio StateUniversity, Columbus, Oh, USA), T Holyoake (University of Glasgow, Glasgow, UK), A Petzer (Barmherzigen Schwestern Linz Hospital, Linz, Austria), and M Barnett, D Forrest, D Hogge, J Lavoie, S Nantel, T Nevill, John Shepherd, K Song, H Sutherland and C Toze (Leukemia/BMT Program of British Columbia, Vancouver, BC, Canada) for providing patient samples; K Lambie, G Shaw, K Saw, L Zhou, W Y Chan and E Pang for excellent technical assistance; the Terry Fox Laboratory FACS Facility for assistance in cell sorting; the Stem Cell Assay Laboratory for cell processing and cryopreservation of normal and CML samples; D Wytrykush for assistance in preparing the paper; Dr P Lansdorp (Terry Fox Laboratory) and StemCell Technologies (Vancouver, BC, Canada) for antibodies and culture reagents, and Novartis (Basel, Switzerland) for the IM.
This work was supported in part by grants from the Cancer Research Society and the Leukemia & Lymphoma Society of Canada (to XJ), from the National Cancer Institute of Canada (with funds from the Canadian Cancer Society and the Terry Fox Foundation to AE, XJ and CE) and Genome British Columbia and the NIH (to AE and CE). X Jiang is a Michael Smith Foundation for Health Research Scholar. Y Zhao was a recipient of a Stem Cell Network Fellowship and a Leukemia & Lymphoma Society of Canada Fellowship.
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Jiang, X., Zhao, Y., Smith, C. et al. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia 21, 926–935 (2007). https://doi.org/10.1038/sj.leu.2404609
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DOI: https://doi.org/10.1038/sj.leu.2404609
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