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| Status |
Public on Sep 08, 2018 |
| Title |
Defective transcription elongation in a subset of cancers confers immunotherapy resistance (human ChIP-Seq) |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
The nature and the role of global transcriptional deregulations in cancers are not fully understood. We report a phenotype in a significant portion of cancers characterized by widespread defects in mRNA transcription elongation (TE). Cancers with TE defects (TEdeff) were characterized by spurious transcription and defective mRNA processing, specifically in a large set of genes characterized by long genomic length, poised promoters and inducible expression. As such, signaling pathways regulated by such genes, such as interferon/JAK/STAT and TNF/NF-κB pathways, were consistently suppressed in TEdeff tumors. Remarkably, TEdeff significantly correlated with the poor response and outcome in immunotherapy, but not chemo- or targeted therapy, -treated renal cell carcinoma and metastatic melanoma patients in 4 different cohorts. Importantly, forced pharmacologic or genetic induction of TEdeff in tumor cells impaired the expression of the interferon/JAK/STAT and TNF/NF-κB pathways, and imposed resistance to the innate and adaptive anti-tumor immune responses and checkpoint inhibitor therapy in vivo. Therefore, defective TE is a novel epigenetic mechanism in the tumor arsenal of immune resistance tools, which warrants its assessment in cancer patients undergoing immunotherapy.
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| Overall design |
Chip sequencing was performed on UACC-812 (transcription elongation defects Tedeff +ve) cancer cell line and T47D (transcription elongation defects Tedeff -ve) cell ine to quantiufy the effect that transcriptional elongation defect has on genome wide distribution of RNA pol2 and RNA pol2-Ser5 in cancers.
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| Contributor(s) |
Modur V, Singh N, Mohanty V, Chung E, Muhammad B, Choi K, Chen X, Chetal K, Ratner N, Salomonis N, Weirauch MT, Waltz S, Huang G, Privette-Vinnedge L, Park J, Janssen EM, Komurov K |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Sep 07, 2018 |
| Last update date |
Mar 27, 2019 |
| Contact name |
Kakajan Komurov |
| E-mail(s) |
komurovlab@gmail.com
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| Organization name |
Cincinnati Children's Hospital
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| Department |
Division of Experimental Hematology & Cancer Biology
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| Street address |
3333 Burnet Ave OH 45229
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| City |
Cincinnati |
| State/province |
OH |
| ZIP/Postal code |
45206 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE119679 |
Defective transcription elongation in a subset of cancers confers immunotherapy resistance |
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| Relations |
| BioProject |
PRJNA489890 |
| SRA |
SRP160394 |
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