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Levels of glucocorticoid receptor and its ligand determine sensitivity and kinetics of glucocorticoid-induced leukemia apoptosis

Leukemia volume 23, pages 820–823 (2009)Cite this article

A Corrigendum to this article was published on 15 April 2009

Glucocorticoid(GC)-induced apoptosis is an essential component in the treatment of lymphoid malignancies, most notably childhood acute lymphoblastic leukemia (ALL). Determining the extent of GC sensitivity/resistance has considerable clinical implications as it might be a relevant parameter in possible future patient- and tumor-adapted therapy regimens directed towards reducing the serious side effects of GC long-term therapy without affecting its anti-tumor efficacy. The most apical molecule in the GC-induced cell death pathway is the GC receptor (GR), a ligand-activated transcription factor of the large nuclear receptor family that, upon ligand binding translocates into the nucleus where it affects the expression of a large number of genes.1 GR expression varies between different ALL cells and is further the subject of cell context-dependent positive and negative feedback regulation.2 Although the apoptotic response clearly depends on the presence of a wild type GR, it is not understood to what extent differences in GR levels and GR auto-regulation influence sensitivity to GC-induced apoptosis.

GC resistance in in vitro models has been shown to result from mutations in the GR gene or lack of GR auto-induction3 a phenomenon seen in several GC-sensitive ALL cell lines2, 4 and some children with T-ALL.5 GR mutations are however, rarely seen in samples from patients at relapse.6 Whether basal GR levels and/or GR auto-induction might contribute to GC resistance in patients is controversial. In the older literature, GR levels correlated with treatment outcome in various lymphoid malignancies including ALL. More recently, one study showed that a higher number of GR binding sites was associated with a larger percent change in absolute peripheral blood blasts after a 3-day treatment with corticosteroids7 but others concluded that GC sensitivity is independent of basal GR expression and/or GR auto-induction in childhood ALL patients.8

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Authors and Affiliations

  1. Division of Molecular Pathophysiology, Biocenter, Medical University of Innsbruck, Tyrol, Austria

    G Gruber, M Carlet, C Ploner & R Kofler

  2. Tyrolean Cancer Research Institute, Innsbruck, Austria

    G Gruber, M Carlet, E Türtscher, B Meister & R Kofler

  3. Department of Pediatrics, Medical University of Innsbruck, Austria

    B Meister

  4. Northern Institute for Cancer Research, Newcastle upon Tyne, UK

    J A E Irving

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  1. G Gruber
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  2. M Carlet
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  6. C Ploner
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  7. R Kofler
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Correspondence to R Kofler.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Gruber, G., Carlet, M., Türtscher, E. et al. Levels of glucocorticoid receptor and its ligand determine sensitivity and kinetics of glucocorticoid-induced leukemia apoptosis. Leukemia 23, 820–823 (2009). https://doi.org/10.1038/leu.2008.360

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