Characterization of cytosolic and nuclear glucocorticoid-binding components in human leukemic lymphocytes.

Almost 30 years have elapsed since glucocorticoids were first used to treat human leukemias and lymphomas (6, 7, 9). However, the mechanism of the lympholytic effect remains to be determined. While glucocorticoids cause numerous bio chemical alterations in CS3 lymphocytes, no clear relationship has been established between these changes and the lethal action of the corticosteroids (36). Regardless of the actual mechanism involved, there is considerable evidence that glu cocorticoid effects on leukemic cells are initiated by interaction of the steroid with a specific intracellular binding protein or receptor (28). The hormone:receptor complex then undergoes a change in conformation, generally termed †̃ †̃activation,' †̃ that enables it to bind to the nucleus. This interaction presumably initiates the events that lead to phenotypic expression of the hormone effects (45). Lippman et a!. (15) detected glucocorticoid receptors in cytosol from lymphoblasts of 22 patients with CS acute lym phoblastic leukemia and showed that lymphoblasts from 6 patients in relapse who were refractory to steroid treatment contained little or no cytoplasmic glucocorticoid receptor. How ever, studies with a large number of experimental and human leukemias (1, 18, 28, 29, 37, 40, 46) indicate thatthe presence of glucocorticoid receptor, or even of receptor binding to the nucleus, is not sufficient to guarantee steroid sensitivity. In deed, a recent survey by Crabtree et a!. (8) suggests that cells of most, if not all, hematological cancers will be found to contain glucocorticoid receptors. Our own studies (37) as well as those of Bourgeois et a!. (2) and of McPartland et a!. (18) revealed striking differences in nuclear-glucocorticoid interactions between CS and CR mouse tumor lymphocytes. Furthermore, we found (35) that cytoplas mic and nuclear glucocorticoid-binding components from CS P1798 lymphocytes were considerably larger and more asym metrical than the complexes in CR cells. Yamamoto et a!. (46) had previously shown pronounced physicochemical differ ences between cytoplasmic @†̃H]dexamethasone:receptor com plexes from CS 5.49 mouse lymphoma cells and those from certain classes of CR mutants. However, except for a few