1. ¹Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada
2. ²Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
3. ³Department of Medicine, University of British Columbia, Vancouver, BC, Canada
4. ⁴Department of Hematology, University of Poitiers, Poitiers, France
5. ⁵Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

Correspondence: Dr X Jiang, Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3. E-mail: xjiang@bccrc.ca

Received 9 November 2006; Revised 2 January 2007; Accepted 17 January 2007; Published online 1 March 2007.

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. p210^BCR-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.