Low Glucocorticoid Receptor α/β Ratio in T-cell Lymphoblastic Leukemia

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 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.

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

“…Interestingly, we show that protein expression of GR␤ is more abundant in mouse lymphoma cells compared with GR␣. Similarly, high expression levels of GR␤ have been reported in immune cells of lupus (20) and leukemia (19) patients, suggesting that a leading target for inhibiting growth in these cells would be GR␤. Here we show that siRNA targeting of GR␤ in MEF cells concomitantly increased PTEN expression.…”

“…Ascending levels of GR␤ in asthma patients cause many disease complications, including GC resistance that can verge to a complete loss of drug response (18). Importantly, both leukemia (19) and systemic lupus erythematosus (20) have been linked to high levels of GR␤, which may underlie the exacerbated immune cell growth observed in these patients. How GR␤ regulates growth is unknown, but the mechanism may involve inhibition of GR␣-induced apoptosis or direct GR␤ epigenetic signaling.…”

Glucocorticoid receptor alpha, beta and gamma expression vs in vitro glucocorticod resistance in childhood leukemia

“…32,33 So far, only one study has been published investigating GRa and GRb levels in pediatric leukemia samples. 34 Longui and co-workers found significantly lower GRa/GRb ratios in T-ALL (a subgroup relatively resistant to GCs) than in common/pre-B ALL. However, the number of patients studied was small (nine controls, 13 ALL patients).…”

Etiopatogênese Molecular dos Tumores Corticotróficos

“…Uma outra explicação para a relativa resistência tecido-específica dos corticotrofinomas aos GCs poderia ser uma alteração na expressão das duas isoformas (α e β) do GR, como já é bem caracterizada em outras situações de resistência tecido-específica aos GC, como asma (68,69), artrite reumatóide (70,71) e leucemia linfóide aguda (72,73). Entretanto, estudando uma série de 17 corticotrofinomas, Dahia e cols.…”