Decreased feedback regulation of low density lipoprotein receptor activity by sterols in leukemic cells from patients with acute myelogenous leukemia

Abstract

Leukemic cells from patients with acute myelogenous leukemia (AML) have higher low density lipoprotein (LDL) receptor activity than normal white blood and bone marrow cells. The underlying mechanism behind this is unclear. We studied the inhibitory effect of sterols on induction of LDL-receptor activity in leukemic cells from 27 patients with AML and in white blood cells from 13 healthy individuals. The high affinity degradation rate of 125I-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 without various concentrations of 25-hydroxycholesterol + cholesterol. The median sterol concentration for 50% inhibition (IC50) of induction was more than five times higher for leukemic cells than for normal mononuclear cells. At the highest sterol concentration (0.400 microg/mL 25-hydroxycholesterol + 8 microg/mL cholesterol), the LDL-receptor activity was abolished in cells from all healthy individuals while the induction of LDL-receptor activity in cells from three AML patients was unaffected. The LDL-receptor activity of leukemic cells, directly after isolation from blood, correlated with IC50 values (r = 0.53, P = 0.007) and WBC counts (r = 0.72, P = 0.0001) but not with cellular cholesterol levels. The results demonstrate decreased feedback regulation of LDL-receptor activity by sterols in AML cells and support the conclusion that elevated LDL-receptor activity is associated with sterol resistance and cell proliferation. The findings are of potential interest for diagnosis and specific treatment of leukemia.