PI3Kδ inhibition potentiates glucocorticoids in B-ALL by decreased receptor phosphorylation and enhanced gene regulation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA890175 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21890600_1.fastq.gz | Fastqsanger.gz | |||
| SRR21890600_2.fastq.gz | Fastqsanger.gz | |||
| SRR21890601_1.fastq.gz | Fastqsanger.gz | |||
| SRR21890601_2.fastq.gz | Fastqsanger.gz | |||
| SRR21890602_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 36 |
Similar Datasets
Project description:Glucocorticoids, including dexamethasone and prednisone, are key components of therapy for B-lymphoblastic leukemia (B-ALL) that work through the glucocorticoid receptor (GR). However, glucocorticoids are not effective for all patients, leading to poor outcomes, and the high doses used in chemotherapy cause many toxicities. We have shown that inhibition of the leukocyte restricted PIK3δ is a promising way to specifically enhance glucocorticoids in B-ALL, with the potential to improve outcomes without increasing toxicities. Here, we show that the PI3Kδ inhibitor idelalisib potentiates both prednisolone and dexamethasone in both B-ALL cell lines and primary patient specimens, particularly at sub-saturating doses. Potentiation is partially explained by a widespread enhancement of glucocorticoid gene regulation, including effector genes that drive B-ALL cell death. Idelalisib causes a reduction in direct phosphorylation of GR at S203 and S226. Ablation of these phospho-acceptor sites enhances glucocorticoid potency. Phosphorylation of S226 inhibits GR DNA binding, indicating that PI3Kδ mediated phosphorylation directly inhibits GR function in part though reduction of DNA binding affinity. Thus, PI3Kδ inhibition improves glucocorticoid efficacy in B-ALL in part by decreasing GR phosphorylation and enhancing DNA binding and downstream gene regulation. Identification of this and other contributing mechanisms will help identify patients who can most benefit clinically from this combination therapy.
2022-10-18 | GSE215385 | GEO
Project description:Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases (IMIDs). However, molecular mechanisms underlying their anti inflammatory mode of action have remained incompletely understood. Here we show that the anti-inflammatory properties of glucocorticoids involve a reprogramming of the mitochondrial metabolism of macrophages, which results in an increased and sustained production of the anti-inflammatory metabolite itaconate and a consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex where glucocorticoids provoke an increase in activity and allow an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. Artificial block of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, in contrast, interferes with the anti-inflammatory effects of glucocorticoids and accordingly abrogates their beneficial effects during a diverse range of preclinical models of IMIDs. Our findings provide important additional insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the future design of novel classes of anti-inflammatory drugs.
2024-02-19 | GSE250274 | GEO
Project description:Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases (IMIDs). However, molecular mechanisms underlying their anti inflammatory mode of action have remained incompletely understood. Here we show that the anti-inflammatory properties of glucocorticoids involve a reprogramming of the mitochondrial metabolism of macrophages, which results in an increased and sustained production of the anti-inflammatory metabolite itaconate and a consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex where glucocorticoids provoke an increase in activity and allow an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. Artificial block of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, in contrast, interferes with the anti-inflammatory effects of glucocorticoids and accordingly abrogates their beneficial effects during a diverse range of preclinical models of IMIDs. Our findings provide important additional insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the future design of novel classes of anti-inflammatory drugs.
2024-02-19 | GSE250273 | GEO
Project description:Glucocorticoids, including dexamethasone and prednisone, are the cornerstone of B-lymphoblastic leukemia (B-ALL) therapy. Because response to glucocorticoids alone predicts overall outcomes for B-ALL, enhancing glucocorticoid potency is a route to improving outcomes. However, systematic toxicities prevent the use of higher dose and more potent glucocorticoids. We therefore took a functional genomic approach to identify targets to enhance glucocorticoid activity specifically in B-ALL cells. Here we show that inhibition of the lymphoid-restricted PI3Kδ, signaling through the RAS/MAPK pathway, enhances both prednisone and dexamethasone activity in almost all ex vivo B-ALL specimens tested. This potentiation is most synergistic at sub-saturating doses of glucocorticoids, approaching the EC50. Potentiation correlates with global enhancement of glucocorticoid-induced gene regulation, including regulation of effector genes that drive B-ALL cell death. Idelalisib reduces phosphorylation of the glucocorticoid receptor (GR) at MAPK1/ERK2 targets S203 and S226, and ablation of these phospho-acceptor sites enhances glucocorticoid potency. We further show that phosphorylation of S226 reduces the affinity of GR for DNA in vitro, which impairs DNA binding. We therefore propose that PI3Kδ inhibition improves glucocorticoid efficacy in B-ALL in part by decreasing GR phosphorylation, increasing DNA binding affinity, and enhancing downstream gene regulation. The overall enhancement of GR function suggests that idelalisib will provide benefit to most patients with B-ALL by improving outcomes for patients whose disease is less responsive to glucocorticoid-based therapy, including high-risk disease, and allowing less toxic glucocorticoid-sparing strategies for patients with standard-risk disease.
| S-EPMC9934697 | biostudies-literature
Project description:Glucocorticoids are the cornerstone of B-lymphoblastic leukemia (B-ALL) therapy. Because response to glucocorticoids alone predicts overall outcomes for B-ALL, enhancing glucocorticoid potency should improve treatment. We previously showed that inhibition of the lymphoid-restricted PI3Kδ with idelalisib enhances glucocorticoid activity in B-ALL cells. Here, we show that idelalisib enhances glucocorticoid potency in 90% of primary B-ALL specimens and is most pronounced at sub-saturating doses of glucocorticoids near the EC50. Potentiation is associated with enhanced regulation of all glucocorticoid-regulated genes, including genes that drive B-ALL cell death. Idelalisib reduces phosphorylation of the glucocorticoid receptor (GR) at PI3Kδ/MAPK1 (ERK2) targets S203 and S226. Ablation of these phospho-acceptor sites enhances sensitivity to glucocorticoids with ablation of S226 in particular reducing synergy. We also show that phosphorylation of S226 reduces the affinity of GR for DNA in vitro. We propose that PI3Kδ inhibition improves glucocorticoid efficacy in B-ALL in part by decreasing GR phosphorylation, increasing DNA binding affinity, and enhancing downstream gene regulation. This mechanism and the response of patient specimens suggest that idelalisib will benefit most patients with B-ALL, but particularly patients with less responsive, including high-risk, disease. This combination is also promising for the development of less toxic glucocorticoid-sparing therapies.
| S-EPMC10778422 | biostudies-literature
Project description:Wnt-signaling potentiates nevogenesis.
| PRJNA202396 | ENA
Project description:Glucocorticoids Promote Breast Cancer Metastasis
| PRJNA513860 | ENA
Project description:Glucocorticoids regulate murine megakaryocyte transcriptome
| PRJNA817170 | ENA
Project description:Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process. Metabolic heterogeneity has also been observed, yet its role for cancer progression is less explored. Here, we discover that loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumors of breast cancer patients is associated with decreased metastasis free survival time. In mice, circulating tumor cells and early metastatic lesions are enriched with PHGDH low cancer cells and silencing PHGDH in primary tumors increases metastasis formation. Mechanistically, PHGDH protein interacts with the glycolytic enzyme phosphofructokinase (PFK) and the loss of this interaction activates the hexosamine – sialic acid pathway, which provides precursors for protein glycosylation. Consequently, aberrant protein glycosylation including increased sialylation of integrin αvβ3 occurs, which potentiates cell migration and invasion. Inhibition of sialic acid metabolism counteracts the metastatic capacity of PHGDH low cancer cells. In conclusion, while the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. Thus, the presence of PHDGH heterogeneity in primary tumors may be considered a sign of tumor aggressiveness.
2022-03-30 | GSE198380 | GEO
Project description:Glucocorticoids are the cornerstone of asthma and other inflammatory disease therapy. Resistance or insensitivity to glucocorticoids presents a substantial and challenging clinical problem. MicroRNAs are emerging as central regulators of inflammation, but it is not clear whether they could augment or attenuate glucocorticoid responses. We aimed to identify microRNAs that regulate cytokine and chemokine expression in airway epithelial cells and whether these miRNAs are subject to the effects of glucocorticoids. MicroRNAomic analyses of primary bronchial epithelial cells and the A549 airway epithelial cell line identified 7 miRNAs that were altered by inflammatory cytokine treatment and 22 that were regulated by glucocorticoids (n=3 for each treatment). miR-146a emerged as a central candidate, whose expression was induced by TNF-alpha and repressed by glucocorticoids. Its role as a candidate in asthmatic inflammation was supported by expression profiling in human asthmatics, which showed that plasma miR-146a expression was elevated in asthma and associated with measures related to worse asthma outcomes, including elevated blood eosinophil counts, higher asthma control questionnaire scores, and need for higher doses of inhaled glucocorticoids. However, transfection of miR-146a in A549 cells treated with TNF-alpha +/- glucocorticoids produced an anti-inflammatory effect and with increased efficacy of glucocorticoids. We propose a model whereby miR-146a is induced by inflammatory conditions as a feedback mechanism to limit inflammation. Glucocorticoids may limit this regulatory pathway by preventing miR-146a expression. Consequently, exogenous administration of miR-146a could be a novel therapeutic strategy to enhance effects of glucocorticoids.
2018-11-01 | GSE120758 | GEO