Growth Factor Stimulation Reduces Residual Quiescent Chronic Myelogenous Leukemia Progenitors Remaining after Imatinib Treatment

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Abstract
The BCR/ABL tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of chronic myelogenous leukemia (CML) but fails to eliminate all leukemia cells. Residual leukemia stem and progenitor cells persist in imatinib-responsive patients and may be a potential source of relapse. Previous studies indicate that imatinib preferentially targets dividing cells, and nondividing progenitor cells are resistant to imatinib-mediated apoptosis. We investigated whether growth factor stimulation of progenitor proliferation could reduce the number of residual nondividing cells remaining after imatinib treatment. CML and normal CD34+ cells were labeled with 5-(and 6-)-carboxyfluorescein diacetate succinimidyl ester (CFSE) to track cell division and cultured in low or high concentrations of growth factor to determine effects of growth factor stimulation on nondividing cells. High growth factor concentrations significantly enhanced CML proliferation with or without imatinib treatment and significantly reduced the number of viable, nondividing CFSE bright cells remaining after imatinib exposure. Stimulation with high growth factor before imatinib treatment further reduced the number of residual nondividing CML CD34+ cells. Importantly, clinically achievable concentrations of granulocyte macrophage colony-stimulating factor alone or in combination with granulocyte colony-stimulating factor also significantly reduced nondividing CML CD34+ cells. These results support the potential efficacy of growth factor stimulation in reducing the residual leukemia progenitor population in imatinib-treated patients. [Cancer Res 2007;67(3):1113–20]