Loss of glucocorticoid receptor expression mediates in vivo dexamethasone resistance in T-cell acute lymphoblastic leukemia
Related Experiment Video
Updated: Dec 28, 2025
Expression of Exogenous Cytokine in Patient-derived Xenografts via Injection with a Cytokine-transduced Stromal Cell Line
Published on: May 10, 2017
Anica M Wandler1, Benjamin J Huang1, Jeffrey W Craig2
1Department of Pediatrics, University of California, San Francisco, CA, USA.
Abstract:
Despite decades of clinical use, mechanisms of glucocorticoid resistance are poorly understood. We treated primary murine T lineage acute lymphoblastic leukemias (T-ALLs) with the glucocorticoid dexamethasone (DEX) alone and in combination with the pan-PI3 kinase inhibitor GDC-0941 and observed a robust response to DEX that was modestly enhanced by GDC-0941. Continuous in vivo treatment invariably resulted in outgrowth of drug-resistant clones, ~30% of which showed markedly reduced glucocorticoid receptor (GR) protein expression. A similar proportion of relapsed human T-ALLs also exhibited low GR protein levels. De novo or preexisting mutations in the gene encoding GR (Nr3c1) occurred in relapsed clones derived from multiple independent parental leukemias. CRISPR/Cas9 gene editing confirmed that loss of GR expression confers DEX resistance. Exposing drug-sensitive T-ALLs to DEX in vivo altered transcript levels of multiple genes, and this response was attenuated in relapsed T-ALLs. These data implicate reduced GR protein expression as a frequent cause of glucocorticoid resistance in T-ALL.
Insights
Mechanisms of glucocorticoid resistance in T-ALL remain unclear. Reduced glucocorticoid receptor (GR) protein expression frequently causes resistance to dexamethasone (DEX) in T-ALL, impacting treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Glucocorticoids are vital in treating T lineage acute lymphoblastic leukemia (T-ALL).
- Mechanisms underlying glucocorticoid resistance in T-ALL are not fully elucidated.
- Understanding resistance is crucial for improving therapeutic outcomes.
Purpose of the Study:
- To investigate the mechanisms of dexamethasone (DEX) resistance in T-ALL.
- To identify molecular alterations leading to treatment failure.
- To explore the role of glucocorticoid receptor (GR) expression in DEX resistance.
Main Methods:
- Treatment of murine T-ALL models with DEX and a PI3K inhibitor.
- In vivo selection for drug-resistant clones.
- Analysis of glucocorticoid receptor (GR) protein expression and Nr3c1 gene mutations.
- CRISPR/Cas9 gene editing to validate findings.
- Transcriptional profiling of DEX-sensitive and resistant T-ALLs.
Main Results:
- Dexamethasone (DEX) treatment led to the outgrowth of resistant T-ALL clones.
- ~30% of resistant clones exhibited reduced glucocorticoid receptor (GR) protein expression.
- Similar low GR protein levels were observed in relapsed human T-ALLs.
- Mutations in the Nr3c1 gene encoding GR were identified in resistant clones.
- Loss of GR expression conferred DEX resistance, confirmed by gene editing.
Conclusions:
- Reduced glucocorticoid receptor (GR) protein expression is a frequent mechanism of DEX resistance in T-ALL.
- Nr3c1 gene alterations contribute to GR downregulation and subsequent resistance.
- These findings highlight GR downregulation as a key factor in T-ALL treatment failure.
Related Concept Videos
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
02:56Treatment Resistant Cancers