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

Abstract:

: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.

journal_name

Ann Hematol

journal_title

Annals of hematology

authors

de Jonge-Peeters SD,van der Weide K,Kuipers F,Sluiter WJ,de Vries EG,Vellenga E

doi

10.1007/s00277-008-0633-2

subject

Has Abstract

pub_date

2009-06-01 00:00:00

pages

573-80

issue

6

eissn

0939-5555

issn

1432-0584

journal_volume

88

pub_type

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