PI3Kδ inhibition potentiates glucocorticoids in B-ALL by decreased receptor phosphorylation and enhanced gene regulation
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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 |
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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.
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Project description:Phosphoinositide 3-kinases (PI3Ks) play a central role in adaptive immunity by transducing signals from the T cell antigen receptor (TCR) via production of PIP3. PI3Kδ is a heterodimer composed of a p110δ catalytic subunit associated with a p85α or p85β regulatory subunit and is preferentially engaged by the TCR upon T cell activation. The molecular mechanisms leading to PI3Kδ recruitment and activation at the TCR signalosome remain unclear. In this study, we have used affinity purification coupled with quantitative mass spectrometry to uncover the p110δ interactome in primary CD4+ T cells. Moreover, we have determined how the PI3Kδ interactome changes upon the differentiation of small naïve T cells into T cell blasts expanded in the presence of IL-2.
2021-03-08 | PXD022607 | Pride
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.
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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.
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Project description:While inputs regulating CD4+ T helper (Th) cell differentiation are well defined, the integration of downstream signaling with transcriptional and epigenetic programs that define Th lineage identity remains incompletely resolved. PI3K signaling is a critical regulator of T cell function; activating mutations affecting PI3Kδ result in an immunodeficiency with multiple T cell defects. Using mice expressing activated PI3Kδ, we found aberrant expression of proinflammatory Th1 signature genes under Th2-inducing conditions, both in vivo and in vitro. This dysregulation was driven by a PI3Kδ-IL-2-Foxo1 signaling amplification loop, fueling Foxo1 inactivation, loss of Th2 lineage restriction, and extensive epigenetic reprogramming. Surprisingly, ablation of Fasl, a Foxo1-repressed gene, normalized both Th2 differentiation and TCR signaling. BioID and imaging revealed Fas interactions with TCR signaling components, which were supported by Fas-mediated potentiation of TCR signaling that could occur in the absence of FADD. Our results highlight Fas-FasL signaling as a critical intermediate in phenotypes driven by activated PI3Kδ, thereby linking two key pathways of immune dysregulation.
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Project description:Phosphoinositide 3-kinase δ (PI3Kδ) plays key roles in lymphocytes and inhibitors targeting this PI3K have been approved for hematological malignancies. While preclinical data in hematological and solid tumor models have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumor immunity, the impact of PI3Kδi in human solid tumors remains unknown. Here, we assessed the effects of the PI3Kδi AMG319 in patients with early stage head and neck cancer in a neoadjuvant, double-blind and placebo-controlled randomised phase-II trial. We find that PI3Kδ inhibition decreases tumor-infiltrating TREG cells and causes heightened cytotoxic potential of tumor-infiltrating CD8+ and CD4+ T cells. Loss of intratumoral TREG cells and an increase in the frequency of activated TREG cells in the blood post-treatment are indicative of systemic effects on TREG cell tissue retention and maintenance. At the chosen AMG319 dosing, the occurrence of immune-related adverse events caused treatment discontinuation in 43% of drug-treated patients, further suggestive of systemic effects on TREG cells. Consistent with this notion, in a murine syngeneic tumor model, PI3Kδi caused a decrease in TREG cells in both tumor and non-malignant tissues and affected TREG subtype composition, maintenance and functionality.
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Project description:Phosphoinositide 3-kinase δ (PI3Kδ) plays key roles in lymphocytes and inhibitors targeting this PI3K have been approved for hematological malignancies. While preclinical data in hematological and solid tumor models have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumor immunity, the impact of PI3Kδi in human solid tumors remains unknown. Here, we assessed the effects of the PI3Kδi AMG319 in patients with early stage head and neck cancer in a neoadjuvant, double-blind and placebo-controlled randomised phase-II trial. We find that PI3Kδ inhibition decreases tumor-infiltrating TREG cells and causes heightened cytotoxic potential of tumor-infiltrating CD8+ and CD4+ T cells. Loss of intratumoral TREG cells and an increase in the frequency of activated TREG cells in the blood post-treatment are indicative of systemic effects on TREG cell tissue retention and maintenance. At the chosen AMG319 dosing, the occurrence of immune-related adverse events caused treatment discontinuation in 43% of drug-treated patients, further suggestive of systemic effects on TREG cells. Consistent with this notion, in a murine syngeneic tumor model, PI3Kδi caused a decrease in TREG cells in both tumor and non-malignant tissues and affected TREG subtype composition, maintenance and functionality.
2022-03-02 | GSE166149 | GEO
Project description:Human neutrophils and neutrophil-like cells were differentiated from HL-60 cells. Cells were treated with glucocorticoids, dexamethasone or prednisolone, for proteome and phosphoproteome analysis.
2026-01-15 | PXD064627 | Pride