The use of statins in acute myeloid leukemia

PhD ceremony: Ms. K. van der Weide, 14.45 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: The use of statins in acute myeloid leukemia

Promotor(s): prof. E. Vellenga, prof. E.G.E. de Vries en prof. F. Kuipers

Faculty: Medical Sciences

 

Patients with acute myeloid leukemia (AML) display a dysfunctional cholesterol metabolism in their bone marrow cells, as well as increased cholesterol levels in these AML cells upon in vitro exposure to chemotherapy. This is expected to protect the cells from cytotoxic treatment effects. Intervention with this protective pathway is therefore a potential attractive means to improve therapeutic outcome. Statins inhibit cholesterol synthesis by blocking HMG-CoA reductase, the rate-controlling enzyme of the mevalonate pathway. We showed that combining statins with standard chemotherapy or a farnesyltransferase inhibitor induces more cytotoxicity in AML bone marrow samples than the separate compounds. However, a subset of patient samples appeared to be relatively resistant to statin treatment. To distinguish sensitive from insensitive patients, cell lines with different sensitivities were investigated. It appeared that the differences in response to statins are due to differential effects on the isoprenylation route, rather than the cholesterol synthesis route, of the mevalonate pathway. Summarizing, we demonstrated heterogeneity in the effects of statins in AML cells and patients. Also, we may be able to identify AML patients that will most likely benefit from (combination) treatment with statins.