Glucocorticoid therapy is pivotal in the treatment of acute lymphoblastic leukemia
(ALL); it reduces cell proliferation, promotes cell cycle arrest, and induces cell
death by apoptosis. The sensitivity of leukemic cells to glucocorticoids was previously
related to the cell concentration of 3[H]dexamethasone-binding sites. The latter represents the classic glucocorticoid receptor
(GR) isoform α that binds ligand and modulates the transcription rates of glucocorticoid-responsive
genes. In ALL, lymphoblasts of T-lineage are less sensitive to glucocorticoids than
cells of the B-lineage. The alternatively spliced GR isoform (GRβ), which exerts a
dominant negative effect on GRα-mediated transcriptional activity, has been proposed
as a possible mediator of glucocorticoid resistance. In this study, we determined
the amount of GRα and GRβ in mononuclear cells from 13 newly diagnosed and untreated
children with ALL and 9 controls by quantitative Western analysis. Generally, leukemic
patients expressed 6 times less GRα (ALL = 0.54 ± 1.1; controls = 3.1 ± 0.9; p < 0.01) than controls, but the same amount of GRβ (ALL = 3.62 ± 3.3; controls = 3.6
± 3.4). ALL patients with T-cell disease had a much lower GRα (0.09 ± 0.1; p < 0.01) but a similar or slightly higher GRβ (5.98 ± 3.9; p = 0.1) expression than controls, with a GRα/GRβ ratio 15 times smaller than controls.
Mononuclear leukocytes of T-cell lineage expressed significantly lower GRα (p = 0.04) and higher GRβ (p < 0.01) than cells of the pre-B immunophenotype, with a 10 times smaller ratio. We
conclude that the combination of low GRα and normal-to-high GRβ expression in leukemic
lymphoblasts might represent one of the mechanisms responsible for their reduced glucocorticoid
sensitivity; this is more pronounced in T-lineage cells.
Key words
Glucocorticoid - Receptor - Acute Leukemia - Glucocorticoid - Sensitivity - Glucocorticoid
Resistance
