Proliferation of CML primitive and committed progenitors is suppressed in cells exposed to SKI-606. CFSE labeling assays were used to measure effects of SKI-606 or imatinib on cell division of CML progenitors. CFSE-labeled cells were sorted for CD34 and CD38 expression to yield primitive (CD34⁺CD38⁻) and committed (CD34⁺CD38⁺) progenitors. Cells were analyzed by FACS for CFSE fluorescence after exposure to inhibitors at the indicated concentrations for 96 hours. (A) Representative CFSE plots for SKI-606 (0.5 μM) and imatinib (5 μM) treated CML CD34⁺38⁻ primitive and CD34⁺CD38⁺ committed progenitors. The calculated proliferation index (PI) for each plot is indicated. (B,C) Compiled data for proliferation of CML and normal primitive progenitors, respectively. (D,E) CML and normal committed progenitors, respectively. Proliferation of inhibitor-treated cells is expressed relative to proliferation in the absence of inhibitor treatment. The mean plus or minus SEM values of replicate experiments are shown (n = 4, CML primitive progenitors; n = 5, CML committed progenitors; n = 3, normal primitive and committed progenitors). (B-E) Significant changes in proliferation in response to imatinib (†††P < .001; †P < .05) or SKI-606 (***P < .001) are indicated. (F) Inhibition of CD34⁺CD38⁺ cell proliferation after exposure to imatinib and SKI-606 in combination. Results represent the mean plus or minus SEM of replicate experiments (n = 7). Significant suppression of progenitor proliferation in treated cells compared with controls (**P < .01; *P < .05). (G) The percentage of nondividing (CFSE bright) CML primitive progenitors remaining after exposure to SKI-606 (0.05 to 0.5 μM) or imatinib (5 μM) for 96 hours as determined by flow cytometry.