Low glucocorticoid receptor α/β ratio in T-cell lymphoblastic leukemia

C. A. Longui, A. Vottero, P. C. Adamson, D. E. Cole, T. Kino, O. Monte, G. P. Chrousos

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)401-406
Number of pages6
JournalHormone and Metabolic Research
Volume32
Issue number10
DOIs
Publication statusPublished - 1 Jan 2000

    Fingerprint

Keywords

  • Acute Leukemia
  • Glucocorticoid Receptor
  • Glucocorticoid Resistance
  • Glucocorticoid Sensitivity

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Longui, C. A., Vottero, A., Adamson, P. C., Cole, D. E., Kino, T., Monte, O., & Chrousos, G. P. (2000). Low glucocorticoid receptor α/β ratio in T-cell lymphoblastic leukemia. Hormone and Metabolic Research, 32(10), 401-406. https://doi.org/10.1055/s-2007-978661