MULTILEVEL REGULATION OF LOW-DENSITY-LIPOPROTEIN RECEPTOR AND 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE GENE-EXPRESSION IN NORMAL ANDLEUKEMIC-CELLS

Altered cholesterol homeostasis has been noted in malignant cells, whi ch led us to explore the regulation of cholesterol metabolism in norma l and leukemic cells. The mean low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activiti es were fivefold and threefold higher in mononuclear blood cells from 33 patients with leukemia, compared with cells from 23 healthy subject s, whereas elevations in RNA levels were twofold and 40% only. The act ivities of the two proteins correlated in normal cells (r = .46), wher eas an inverse correlation was found in leukemic cells (r = -.40). Rel atively weak correlations were found between LDL receptor RNA levels a nd receptor activity in normal (r = .48) and leukemic cells (r = .49), and HMG-CoA reductase RNA levels correlated (r = .53) with reductase activity in leukemic cells only. The ratios of protein activities to R NA levels in cells were constant during consecutive blood samplings an d similar in leukemic blood and bone marrow cells from the same indivi dual. During cholesterol deprivation, protein activities increased mor e than RNA levels, and leukemic cells with high LDL receptor activity showed a partial resistance to the suppressing effect of sterols on LD L receptor gene expression. The results demonstrate that LDL receptor RNA levels alone can not explain variation in receptor activity, sugge sting post-RNA regulation of LDL receptor expression, similar to what has been described for HMG-CoA reductase. Taken together, the present results suggest multilevel regulation of both proteins and demonstrate that each cell clone, normal or malignant, has a unique ratio of prot ein activity to RNA level. Leukemic cells, in contrast to normal cells , can meet increased cholesterol requirements by either elevated LDL r eceptor activity or increased cholesterol synthesis, which is of poten tial interest for diagnosis and specific treatment of leukemia. (C) 19 94 by The American Society of Hematology.