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Expression of DND41 cell lines treated with 1µM Dexamethasone for 24h after shPTEN infection

ABSTRACT: Glucocorticoid resistance is a major driver of therapeutic failure in T-cell acute lymphoblastic leukemia (T-ALL). Here we identify the AKT1 kinase as a signaling factor driving glucocorticoid resistance in T-ALL. Mechanistically, AKT1 directly phosphorylates the glucocorticoid receptor NR3C1 protein and blocks glucocorticoid-induced NR3C1 transcription by inhibiting glucocorticoid-induced NT3C1 translocation to the nucleus. Consistently, pharmacologic inhibition of AKT1 increases the response of T-ALL cells to glucocorticoid therapy and effectively reverses glucocorticoid resistance in vitro and in vivo. These results warrant the clinical testing of AKT1 inhibitors and glucocorticoids in combination for the treatment of T-ALL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE41062 | GEO | 2013/10/01

SECONDARY ACCESSION(S): PRJNA175767

REPOSITORIES: GEO

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Expression of DND41 cell lines treated with 1M-BM-5M Dexamethasone for 24h after shPTEN infection

Project description:Glucocorticoid resistance is a major driver of therapeutic failure in T-cell acute lymphoblastic leukemia (T-ALL). Here we identify the AKT1 kinase as a signaling factor driving glucocorticoid resistance in T-ALL. Mechanistically, AKT1 directly phosphorylates the glucocorticoid receptor NR3C1 protein and blocks glucocorticoid-induced NR3C1 transcription by inhibiting glucocorticoid-induced NT3C1 translocation to the nucleus. Consistently, pharmacologic inhibition of AKT1 increases the response of T-ALL cells to glucocorticoid therapy and effectively reverses glucocorticoid resistance in vitro and in vivo. These results warrant the clinical testing of AKT1 inhibitors and glucocorticoids in combination for the treatment of T-ALL. Gene Expression Analysis of DND41 cell lines infected with shPTEN or shLUC and treated with 1M-BM-5M Dexamethasone vs DMSO for 24h, in triplicate.

2013-10-01 | E-GEOD-41062 | biostudies-arrayexpress

Reversal of glucocorticoid resistance by AKT inhibition in T-ALL

Project description:Glucocorticoid resistance is a major driver of therapeutic failure in T-cell acute lymphoblastic leukemia (T-ALL). Here we used a systems biology approach, based on the reverse engineering of signaling regulatory networks, which identified the AKT1 kinase as a signaling factor driving glucocorticoid resistance in T-ALL. Indeed, activation of AKT1 in T-ALL lymphoblasts impairs glucocorticoid-induced apoptosis. Mechanistically, AKT1 directly phosphorylates the glucocorticoid receptor NR3C1 protein at position S134 and blocks glucocorticoid-induced NR3C1 translocation to the nucleus. Consistently, inhibition of AKT1 with MK-2206 increases the response of T-ALL cells to glucocorticoid therapy both in T-ALL cell lines and in primary patient samples thus effectively reversing glucocorticoid resistance in vitro and in vivo. These results warrant the clinical testing of ATK1 inhibitors and glucocorticoids, in combination, for the treatment of T-ALL. This study includes 228 T-ALL samples of which 117 samples are re-analysis of GSE26713.

2013-05-30 | E-GEOD-32215 | biostudies-arrayexpress

Reversal of glucocorticoid resistance by AKT inhibition in T-ALL

2013-05-30 | GSE32215 | GEO

Loss of Glucocorticoid Receptor Expression Mediates in Vivo Dexamethasone Resistance in T-cell Acute Lymphoblastic Leukemia

Project description: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 pre-existing 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.

2019-12-13 | GSE141967 | GEO

The auophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages

Project description:Glucocorticoids are widely used to treat inflammatory disorders; however, prolonged use of glucocorticoids results in side effects including osteoporosis, diabetes and obesity. Compound A (CpdA), identified as a selective NR3C1/glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1) modulator, exhibits an inflammation-suppressive effect, largely in the absence of detrimental side effects. To understand the mechanistic differences between the classic glucocorticoid dexamethasone (DEX) and CpdA, we looked for proteins oppositely regulated in bone marrow-derived macrophages using an unbiased proteomics approach. We found that the autophagy receptor SQSTM1 but not NR3C1 mediates the anti-inflammatory action of CpdA. CpdA drives SQSTM1 upregulation by recruiting the NFE2L2 transcription factor to its promoter. In contrast, the classic NR3C1 ligand dexamethasone recruits NR3C1 to the Sqstm1 promoter and other NFE2L2-controlled gene promoters, resulting in gene downregulation. Both DEX and CpdA induce autophagy, with marked different autophagy characteristics and morphology. Suppression of LPS-induced Il6 and Ccl2 genes by CpdA in macrophages is hampered upon Sqstm1 silencing, confirming that SQSTM1 is essential for the anti-inflammatory capacity of CpdA, at least in this cell type. Together, these results demonstrate how off-target mechanisms of selective NR3C1 ligands may contribute to a more efficient anti-inflammatory therapy.

2019-06-11 | PXD012121 | Pride

RNA-seq of liver after SHAM or CLP with and without dexamethasone treatment

Project description:Study of the occurrence of glucocorticoid resistance after CLP induced sepsis in mice

2021-02-01 | GSE160795 | GEO

ChIP-seq of liver after SHAM or CLP with and without dexamethasone treatment

Project description:Study of the occurrence of glucocorticoid resistance after CLP induced sepsis in mice

2021-02-01 | GSE161183 | GEO

Thalidomide in Total Therapy 2 Overcomes Inferior Prognosis of Myeloma with Low Expression of the Glucocorticoid Receptor Gene NR3C1

Project description:Purpose: Because dexamethasone remains a key component of myeloma therapy, we wished to examine the correlation of baseline and relapse expression levels of the glucocorticoid receptor gene NR3C1 with other clinical features. Experimental Design: We investigated the clinical impact of gene expression profiling (GEP)–derived expression levels of NR3C1 in 351 patients with GEP data available at baseline and in 130 with data available at relapse, among 668 subjects accrued to Total Therapy 2 (TT2). The effect of the expression of NR3C1 at baseline (previously published under GSE2685) and at relapse was analyzed in the context of treatment (thalidomide vs. no thalidomide) and other clinical parameters.

2012-11-05 | E-GEOD-38627 | biostudies-arrayexpress

RNA-seq of liver after SHAM or CLP with and without dexamethasone treatment [24hrs]

Project description:Study of the occurrence of glucocorticoid resistance after CLP induced sepsis in mice

2021-02-01 | GSE160830 | GEO

The knockdown of maternal glucocorticoid receptor mRNA alters embryo development in zebrafish

Project description:In zebrafish, ovulated oocytes contain both cortisol deposited from the maternal circulation and maternal mRNA for the glucocorticoid receptor (gr mRNA), which is spread as granular structures throughout the central ooplasm. At the 1-cell stage (0.2 hpf), this transcript is relocated by streamers in the blastodisc area and equally partitioned among blastomeres. At 15 hpf, it is replaced by the zygotic transcript. Morpholino knockdown was applied to block translation (grATG1MO or MO2-nr3c1 and grATG2MO or MO3-nr3c1) of both maternal and zygotic gr transcripts, while a missplicing morpholino (grmismMO or MO4-nr3c1) was used to block post-transcriptionally the zygotic transcript alone. MO2-nr3c1 and MO3-nr3c1 (but not MO4-nr3c1) treatment produced craniofacial and caudal malformations in 1-dpf embryos and 5-dpf larvae, which were also affected by pericardial oedema, persistent yolk sac, reduced subintestinal veins, altered neurogenesis and uninflated swim bladder. Such effects were rescued with trout gr2 mRNA. Pangenomic microarray analysis revealed that 114 and 37 highly expressed transcripts were up- and down-regulated, respectively, by maternal GR protein deficiency in 5-hpf embryos. Similar alterations were found at 10 hpf. These effects were confirmed by real-time PCR of 2 up- (casp8, grp1 and igf2a) and 1 down-regulated transcripts (mcm6) evaluated at 4, 8 and 12 hpf. As the contents of transcripts were modified already at 4 hpf, it seems that the lack of GR affects both ways the molecular machinery for the degradation of maternal mRNAs. These results indicate that the maternal gr transcript participates in the maternal programming of zebrafish development. MO2-nr3c1 morphants were compared with MO2-nr3c1-5m morphants at 5 hpf and 10 hpf. MO2-nr3c1 morphants were compared with wild type (WT) at 5 hpf and 10 hpf. MO2-nr3c1 is a morpholino selected to knockdown translation of gr mRNA. MO2-nr3c1-5m is a specific control morpholino.

2011-11-16 | E-GEOD-25517 | biostudies-arrayexpress

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