Variability in responsiveness to lovastatin of the primitive CD34+ AML subfraction compared to normal CD34+ cells.
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 (n = 17) were sorted in CD34(+) and CD34(-) fractions and compared to normal CD34(+/-) cells (n = 7). The percentage of surviving cells upon exposure to lovastatin (25-100 microM) 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 (n = 11) and abnormal (n = 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 CD34(+)CD38(-)AML 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.
de Jonge-Peeters
Susan D P W M
SD
Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
van der Weide
Karen
K
Kuipers
Folkert
F
Sluiter
Wim J
WJ
de Vries
Elisabeth G E
EG
Vellenga
Edo
E
D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D002469:Cell Separation / Q000379:methods*; D002478:Cells, Cultured; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology*; D008148:Lovastatin / Q000494:pharmacology*; D008875:Middle Aged; D016896:Treatment Outcome
D018952:Antigens, CD34; D008148:Lovastatin