Low glucocorticoid receptor alpha/beta ratio in T-cell lymphoblastic leukemia

Citation
Ca. Longui et al., Low glucocorticoid receptor alpha/beta ratio in T-cell lymphoblastic leukemia, HORMONE MET, 32(10), 2000, pp. 401-406
Citations number
44
Categorie Soggetti
Endocrinology, Nutrition & Metabolism
Journal title
HORMONE AND METABOLIC RESEARCH
ISSN journal
00185043 → ACNP
Volume
32
Issue
10
Year of publication
2000
Pages
401 - 406
Database
ISI
SICI code
0018-5043(200010)32:10<401:LGRARI>2.0.ZU;2-P
Abstract
Glucocorticoid therapy is pivotal in the treatment of acute lymphoblastic l eukemia (ALL); it reduces cell proliferation, promotes cell cycle arrest, a nd induces cell death by apoptosis, The sensitivity of leukemic cells to gl ucocorticoids was previously related to the cell concentration of (3)[H]dex amethasone-binding sites. The latter represents the classic glucocorticoid receptor (GR) isoform cr 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 alt ernatively spliced CR isoform (GR beta), which exerts a dominant negative e ffect on GR alpha -mediated transcriptional activity, has been proposed as a possible mediator of glucocorticoid resistance. In this study, we determi ned the amount of GR alpha and GR beta in mononuclear cells from 13 newly d iagnosed and untreated children with ALL and 9 controls by quantitative Wes tern analysis. Generally, leukemic patients expressed 6 times less GR alpha (ALL = 0.54 +/- 1.1; controls = 3.1 +/- 0.9; p < 0.01) than controls, but the same amount of GRP (ALL = 3.62 +/- 3.3: controls = 3.6 +/- 3.4). ALL pa tients with T-cell disease had a much lower GR<alpha> (0.09 +/- 0.1;p < 0.0 1) but a similar or slightly higher GR<beta> (5.98 +/- 3.9: p = 0.1) expres sion than controls, with a GR alpha /GR beta ratio 15 times smaller than co ntrols. Mononuclear leukocytes of T-cell lineage expressed significantly lo wer GR alpha (p = 0.04) and higher CR beta (p < 0.01) than cells of the pre -B immunophenotype, with a 10 times smaller ratio. We conclude that: the co mbination of low GR<alpha> and normal-to-high GR beta expression in leukemi c lymphoblasts might represent one of the mechanisms responsible for their reduced glucocorticoid sensitivity; this is more pronounced in T-lineage ce lls.