Low glucocorticoid receptor alpha/beta ratio in T-cell lymphoblastic leukemia.
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 alpha 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 (GRP), which exerts a dominant negative effect on GRalpha-mediated transcriptional activity, has been proposed as a possible mediator of glucocorticoid resistance. In this study, we determined the amount of GRalpha and GRbeta 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 GRalpha (ALL= 0.54 +/- 1.1; controls = 3.1 +/- 0.9; p < 0.01) than controls, but the same amount of GRbeta (ALL=3.62 +/- 3.3; controls = 3.6 +/- 3.4). ALL patients with T-cell disease had a much lower GRalpha (0.09 +/- 0.1; p < 0.01) but a similar or slightly higher GRbeta (5.98 +/- 3.9; p = 0.1) expression than controls, with a GRalpha/GRbeta ratio 15 times smaller than controls. Mononuclear leukocytes of T-cell lineage expressed significantly lower GRalpha (p = 0.04) and higher GRbeta (p < 0.01) than cells of the pre-B immunophenotype, with a 10 times smaller ratio. We conclude that the combination of low GRalpha and normal-to-high GRbeta expression in leukemic lymphoblasts might represent one of the mechanisms responsible for their reduced glucocorticoid sensitivity; this is more pronounced in T-lineage cells.
Longui
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CA
Section on Pediatric Endocrinology, DEB, NICHD, NIH, Bethesda, USA. fisiolab@santacasasp.org.br
Vottero
A
A
Adamson
P C
PC
Cole
D E
DE
Kino
T
T
Monte
O
O
Chrousos
G P
GP
D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism*; D008297:Male; D010641:Phenotype; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*
D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta