AI Article Synopsis
- Research identified 463 genomic features linked to glucocorticoid resistance in acute lymphoblastic leukemia using a comprehensive analysis of mRNA, miRNA, and other genetic factors.
- A total of 118 overlapping genes were found, including 30 out of 38 known glucocorticoid-resistance genes, along with 14 new genes connected to resistance.
- The study highlighted CELSR2 as a significant player in glucocorticoid resistance, leading to the discovery of a potential new drug combination that could combat resistance in leukemia treatments.
Article Abstract
Identification of genomic and epigenomic determinants of drug resistance provides important insights for improving cancer treatment. Using agnostic genome-wide interrogation of mRNA and miRNA expression, DNA methylation, SNPs, CNAs and SNVs/Indels in primary human acute lymphoblastic leukemia cells, we identified 463 genomic features associated with glucocorticoid resistance. Gene-level aggregation identified 118 overlapping genes, 15 of which were confirmed by genome-wide CRISPR screen. Collectively, this identified 30 of 38 (79%) known glucocorticoid-resistance genes/miRNAs and all 38 known resistance pathways, while revealing 14 genes not previously associated with glucocorticoid-resistance. Single cell RNAseq and network-based transcriptomic modelling corroborated the top previously undiscovered gene, CELSR2. Manipulation of CELSR2 recapitulated glucocorticoid resistance in human leukemia cell lines and revealed a synergistic drug combination (prednisolone and venetoclax) that mitigated resistance in mouse xenograft models. These findings illustrate the power of an integrative genomic strategy for elucidating genes and pathways conferring drug resistance in cancer cells.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467080 | PMC |
| http://dx.doi.org/10.1038/s43018-020-0037-3 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Glucocorticoid Resistance Syndrome in 2 Patients With Diverse Genotype.
JCEM Case Rep
February 2025
University of Utah Health, Division of Endocrinology, Salt Lake City, UT 84108, USA.
Glucocorticoid resistance syndrome (GRS) is caused by inactivating pathogenic variants in the glucocorticoid receptor gene . Reduced glucocorticoid receptor signaling leads to decreased tissue sensitivity to cortisol and resultant biochemical hypercortisolism without the classic clinical features of Cushing syndrome. Patients variably present with signs and symptoms of mineralocorticoid and androgen excess from ACTH overstimulation of the adrenal cortex.
View Article and Find Full Text PDFIL-8 promotes pyroptosis through ERK pathway and mediates glucocorticoid resistance in chronic rhinosinusitis with nasal polyps.
Inflamm Res
January 2025
Institute of Otolaryngology head and neck surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
Objective: This study seeks to elucidate the role and molecular mechanisms of IL-8 in nasal epithelial cell pyroptosis and its impact on glucocorticoid (GC) resistance.
Methods: We assessed the expression of pyroptosis-related biomarkers and IL-8 in tissues and human nasal epithelial cells (hNECs) from both control and nasal polyp patients using western blot. Their localization was determined through immunohistochemistry and immunofluorescence.
Serum CXCL-1 as a predictive biomarker for glucocorticoid resistance in adenoids of patients with adenoid hypertrophy.
Eur Arch Otorhinolaryngol
December 2024
Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, China.
Purpose: The objective of this study was to elucidate the relationship between adenoid hypertrophy (AH) and glucocorticoid resistance, and to investigate the potential reasons for the suboptimal therapeutic response to intranasal glucocorticoids (INS) in pediatric patients with AH.
Methods: The present study enrolled a cohort of 110 patients diagnosed with AH, all of whom underwent adenoidectomy at Renmin Hospital of Wuhan University between June 2023 and September 2023. Immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR) were employed to assess the levels of inflammatory cytokines, and glucocorticoid receptors (GR, including GRα and GRβ) in adenoidal tissues.
Editorial: 46,XX differences of sex development (DSD) outside congenital adrenal hyperplasia (CAH).
Front Endocrinol (Lausanne)
November 2024
Section of Medicine, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
Preclinical and clinical studies on Qin-Zhu-Liang-Xue decoction: insights from network pharmacology and implications for atopic dermatitis treatment.
Front Med
December 2024
Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
To investigate the protective effects and underlying mechanisms of Qin-Zhu-Liang-Xue decoction (QZLX) in atopic dermatitis (AD) and glucocorticoid resistance, we conducted a single-blinded, randomized controlled clinical trial to evaluate the efficacy and safety of this concoction. Network pharmacology analysis was performed and validated through clinical studies. The efficacy, safety, and mechanism of action of QZLX and glucocorticoid receptor (GR) α recombinant protein were assessed in AD mice induced by 2,4-dinitrofluorobenzene (DNFB).
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!