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Purpose: To show whether the inhibitory effects of the cholesterol synthesis inhibitor simvastatin on human CD34 + acute myeloid leukemia (AML) cells can be further promoted by combining it with the farnesyltransferase inhibitor tipifarnib. Experimental Design: Normal CD34 + , AML CD34 + , and CD34 -sorted subfractions, and AML cell lines (TF-1and KG1A) were exposed to simvastatin and tipifarnib. Results: Both simvastatin and tipifarnib showed a cytotoxic effect on AML cell lines, which was additive when used in combination. In primary sorted CD34 + AML cells, a heterogeneous response pattern was observed upon treatment with simvastatin when analyzing cell survival. A group of normal (n = 12) and abnormal (n = 10) responders were identified within the AML CD34 + subfraction when compared with normal CD34 + cells. This distinction was not observed within the AML CD34 -cell fraction.When the CD34 + AML cells were exposed to simvastatin and tipifarnib, a significant enhanced inhibitory effect was shown exclusively in the normal AML responder group, whereas the AML CD34 -cell fractions all showed an enhanced inhibitory effect. The observed heterogeneity in AML responsiveness could not be explained by differences in effects on cholesterol metabolism genes or extracellular signal-regulated kinase phosphorylation in response to simvastatin and tipifarnib treatment. Conclusion:The results suggest that combined treatment with statins and farnesyltransferase inhibitors may be beneficial for a subset of AML patients that can be defined by studying the AML CD34 + fraction.

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