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GSE87716
Homo sapiens
6 Downloadable Samples
Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite current progress in improving patient outcome, MM remains largely incurable. Disease clonal and interpatient heterogeneity has hampered identification of a common underlying mechanism for disease establishment and have slowed the development of novel targeted therapies. Epigenetic aberrations are now emerging as increasingly important in tumorigenesis, thus selective targeting of crucial epigenetic enzymes may provide new therapeutic potential in cancer including MM. Recently, we and others suggested the histone methyltransferase enhancer of zeste homolog 2 (EZH2), to be a potential therapeutic target in MM. Now we show that pharmacological inhibition of EZH2 suppresses the MM cell growth through downregulation of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1and c-MYC. We also show that downregulation of these genes is mediated via reactivated expression of microRNAs with tumor suppressor functions; primarily miR125a-3p and miR320c. Using chromatin immunoprecipitation (ChIP) we demonstrate that miR125a-3p and miR320c are targets of EZH2 and H3K27me3 in MM cell lines and primary MM cells. Our results further highlight the importance of polycomb-mediated silencing in MM to include microRNAs with tumor suppressor activity. This novel role further strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.
Publication Title
EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 6 Downloadable Samples
AB 5500 Genetic Analyzer (Homo sapiens), Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
in this study we define an epigenomic profile of PRC2 (H3K27me3 and bivalent) tragets in four newly diagnosed MM patients. Using Oncomine database we demonstarte that PRC2 targets are underexpressed with advanced ISS stages and correlated to poor outcome. Pharmacological inhibition of UNC1999 showed anti-myeloma potential in vitro by activating the expression genes related to apoptosis and cell differenatiation.
Publication Title
Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 24 Downloadable Samples
NextSeq 500
Description
Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) with asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthma is unclear. Objective: To explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthma. Methods: Primary human bronchial epithelial cell (HBEC) air-liquid interface (ALI) cultures were stimulated with IL-6 and sIL-6R to establish an IL-6TS gene signature. Two separate RNA sequencing (RNA-seq) studies were performed: The “IL-6 vs T2 study” compared gene expression after stimulation with control medium, IL-6, IL-6/sIL-6R and IL-4/IL-13, while the “JAK1-inhibition study” addressed the effect of JAK1 inhibition on IL-6TS induced gene expression. The IL-6TS gene signature was used to stratify lung epithelial transcriptomic data obtained from asthmatics (n=103) in the U-BIOPRED cohorts by hierarchical clustering. Molecular phenotyping was based on the transcriptional profiling of epithelial brushings, pathway analysis and immunohistochemistry analysis of bronchial biopsies. Results: Activation of IL-6TS in HBEC ALI cultures reduced epithelial barrier function and induced a specific epithelial gene signature enriched in airway remodeling genes. The IL-6TS signature identified a subset (n=17) of IL-6TS High asthma patients with increased epithelial expression of IL-6TS inducible genes in absence of increased systemic levels of IL-6 and sIL-6R. The IL-6TS High subset had an increased exacerbation frequency (p=0.028), blood (>300/µl; p=0.0028) and sputum (>20%; p=0.007) eosinophilia, and submucosal infiltration of CD4 T cells, CD8 T cells (p<0.001) and macrophages (p=0.001). In bronchial brushings, TLR pathway genes were up-regulated while the expression of epithelial tight junction genes was reduced (all with q<0.05). Sputum sIL-6R levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, MMP3, IL-8 and IL-1ß (all with q<0.001). Conclusions: Local lung epithelial IL-6TS activation in absence of type 2 airway inflammation defines a novel subset of asthmatics and may drive airway inflammation and epithelial dysfunction in these patients. Overall design: Primary human bronchial epithelial cells grown and differentiated on air-liquid interface were stimulated basolaterally for 24h with cytokines corresponding to IL-6TS (IL-6 + sIL-6R), IL-6 alone, a Type 2 immune response (IL-4 + IL-13) or media alone as non-stimulated control. Each stimulation condition was done in triplicates. Cells were lysed, the RNA isolated and converted into libraries then used for next generation sequencing in order to identify genes that were up- or downregulated in response to the different stimulations.
Publication Title
Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation.
Sample Metadata Fields
Specimen part, Subject
View Samples