DECREASED FEEDBACK-REGULATION OF LOW-DENSITY-LIPOPROTEIN RECEPTOR ACTIVITY BY STEROLS IN LEUKEMIC-CELLS FROM PATIENTS WITH ACUTE MYELOGENOUS LEUKEMIA

Leukemic cells from patients with acute myelogenous leukemia (AML) hav e higher lo iv density lipoprotein (LDL) receptor activity than normal white blood and bone marrow cells. The underlying mechanism behind th is is unclear. We studied the inhibitory effect of sterols on inductio n of LDL-receptor activity in leukemic cells from 27 patients with AML and in white blood cells from 13 healthy individuals. The high affini ty degradation rate of I-125-labeled LDL was determined in mononuclear blood cells directly after isolation from blood and after incubation for 2 days in medium with 10% lipoprotein-deficient serum with or with out various concentrations of 25-hydroxycholesterol + cholesterol. The median sterol concentration for 50% inhibition (IC50) of induction wa s more than five times higher for leukemic cells than for normal monon uclear cells. At the highest sterol concentration (0.400 mu g/mL 25-hy droxycholesterol + 8 mu g/mL cholesterol), the LDL-receptor activity w as abolished in cells from all healthy individuals while the induction of LDL-receptor activity in cells from three AML patients tvas unaffe cted. The LDL-receptor activity of leukemic cells, directly after isol ation from blood, correlated with IC50 values (r = 0.53, P = 0.007) an d WBC counts (r = 0.72, P = 0.0001) but not with cellular cholesterol levels. The results demonstrate decreased feedback regulation of LDL-r eceptor activity by sterols in AML cells and support the conclusion th at elevated LDL-receptor activity is associated with sterol resistance and cell proliferation. The findings are of potential interest for di agnosis and specific treatment of leukemia.