Variability in responsiveness to lovastatin of the primitive CD34 AML subfraction compared to normal CD34 cells

Overview & Synopsis

In the present study, we questioned whether the cholesterol synthesis inhibitor lovastatin potentiates the cytotoxicity of chemotherapeutic agents in the primitive CD34 subpopulation of acute myeloid leukemia (AML) cells. AML mononuclear cells ( = 17) were sorted in CD34 and CD34 fractions and compared to normal CD34 cells ( = 7). The percentage of surviving cells upon exposure to lovastatin (25–100 μM) and/or chemotherapeutics (cytarabin or daunorubicin) was determined with a luminescent cell viability assay. The results demonstrate that the primitive CD34 subpopulation of normal and AML cells displayed a higher sensitivity to lovastatin than the more mature CD34 subpopulation. The combination of lovastatin and chemotherapeutics resulted in a more pronounced inhibitory effect on both subpopulations. In contrast to the homogeneous results in normal CD34 cells, a distinct heterogeneity in lovastatin sensitivity was found in AML samples. Therefore, a group of normal ( = 11) and abnormal ( = 6) responders were identified based on a reduced or increased cell survival compared to normal CD34 cells. This distinction was not only observed in the CD34 AML subfraction but also in CD34CD38AML cells. In the abnormal responder group, 50% of patients presented with unfavorable cytogenetics and significant higher peripheral blast cell counts, which coincided with poor treatment results. In summary, the findings indicate that the primitive subfraction of CD34 AML cells is in the majority of cases affected by lovastatin treatment, which is potentiated when combined with chemotherapeutics. Heterogeneity of the response observed in AML patients allowed identification of a subgroup with poor prognosis.