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Homo sapiens
18 Downloadable Samples
Affymetrix Human Exon 1.0 ST Array [probe set (exon) version (huex10st)
Description
The synthesis and processing of mRNA, from transcription to translation initiation, often requires splicing of intragenic material. The final mRNA composition varies based upon proteins that modulate splice site selection. EWS-FLI1 is an Ewing sarcoma (ES) oncogene with an interactome that we demonstrate to have multiple partners in spliceosomal complexes. We evaluate EWS-FLI1 upon post-transcriptional gene regulation using both exon array and RNA-seq. Genes that potentially regulate oncogenesis including CLK1, CASP3, PPFIBP1, and TERT validate as alternatively spliced by EWS-FLI1. EWS-FLI1 also alters splicing by directly binding to known splicing factors including DDX5, hnRNPK, and PRPF6. Reduction of EWS-FLI1 produces an isoform of g-TERT that has increased telomerase activity compared to WT TERT. The small molecule YK-4-279 is an inhibitor of EWS-FLI1 oncogenic function that disrupts specific protein interactions including DDX5 and RNA helicase A (RHA) that alters RNA splicing ratios. As such, YK-4-279 validates the splicing mechanism of EWS-FLI1 showing alternatively spliced gene patterns that significantly overlap with EWS-FLI1 reduction and WT human mesenchymal stem cells. Exon array analysis of 75 ES patient samples show similar isoform expression patterns to cell line models expressing EWS-FLI1, supporting the clinical relevance of our findings. These experiments establish systemic alternative splicing as an oncogenic process modulated by EWS-FLI1. EWS-FLI1 modulation of mRNA splicing may provide insight into the contribution of splicing towards oncogenesis, and reciprocally, EWS-FLI1 interactions with splicing proteins may inform the splicing code.
Publication Title
Oncogenic fusion protein EWS-FLI1 is a network hub that regulates alternative splicing.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 3 Downloadable Samples
Illumina HiSeq 2500
Description
A chimeric fusion between the RNA binding protein EWS and the ETS family transcription factor FLI1 (EWS-FLI1), created from a chromosomal translocation, is implicated in driving the majority of Ewing sarcomas (ES) by modulation of transcription and alternative splicing. The small molecule YK-4-279 inhibits EWS-FLI1 function and induces apoptosis. We tested 69 anti-cancer drugs in combination with YK-4-279 and found that vinca alkaloids exhibited synergy with YK-4-279 in five ES cell lines. The combination of YK-4-279 and vincristine reduced tumor burden and increased survival in mice bearing ES xenografts. We determined that independent drug-induced events converged to cause this synergistic therapeutic effect. YK-4-279 rapidly induced G2/M arrest, increased the abundance of cyclin B1, and decreased EWS-FLI1–mediated expression of microtubule-associated proteins, which rendered cells more susceptible to microtubule depolymerization by vincristine. YK-4-279 reduced the expression of the EWS-FLI1 target gene encoding ubiquitin ligase UBE2C, and this in part contributed to the increase in cyclin B1. Biochemical assays revealed that YK-4-279 also increased the abundance of proapoptotic isoforms of MCL1 and BCL2, presumably through inhibition of alternative splicing by EWS-FLI1, thus promoting cell death in response to vincristine. Thus a combination of vincristine and YK-4-279 might be therapeutically effective in ES patients. Overall design: Examination of mRNA profiles of TC32 on knockdown of EWS-FLI1 or treatment with YK-4-279: 3 samples Total: 1 TC32 WT Control, 1 TC32 shEF, 1 TC32 YK
Publication Title
Inhibition of the oncogenic fusion protein EWS-FLI1 causes G<sub>2</sub>-M cell cycle arrest and enhanced vincristine sensitivity in Ewing's sarcoma.
Sample Metadata Fields
Cell line, Subject
View Samples- Mus musculus
- 47 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Transcriptome analysis of mRNA samples from a cohort of mice with histopathologically diagnosed Undifferentiated Myeloid Leukemia.
Publication Title
Analyzing tumor heterogeneity and driver genes in single myeloid leukemia cells with SBCapSeq.
Sample Metadata Fields
Sex, Age, Specimen part, Disease, Disease stage
View Samples- Mus musculus
- 5 Downloadable Samples
- Ion Torrent Proton
Description
Mus musculus (house mouse) Myeloid Leukemia RNA-Seq
Publication Title
Analyzing tumor heterogeneity and driver genes in single myeloid leukemia cells with SBCapSeq.
Sample Metadata Fields
No sample metadata fields
View Samples
GSE64385- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
These experiments were designed as a benchmark tool for deconvolution methods. 5 immune cell populations were sorted from 3 healthy donors' peripheral bloods. Peripheral Blood Mononuclear Cells (PBCMs) and PolymorphoNuclear Cells (PMN) were separated using gradient centrifugation. T cells (DAPI-/CD3+/CD14-/CD19-/CD56-), monocytes (DAPI-/CD3-/CD14+/CD19-/CD56-), B cells (DAPI-/CD3-/CD14-/CD19+/CD56-) and NK cells (DAPI-/CD3-/CD14-/CD19-/CD56+) were FACS-sorted from PBMCs and neutrophils (DAPI-/CD66b+/CD19-/CD3-/CD56-/CD14-) were sorted from PMNs. RNA was extracted from the purified cell population, as well as from the HCT116 colon cancer cell line. RNAs from pure populations were then mixed in various proportions.
Publication Title
Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 9 Downloadable Samples
- IlluminaHiSeq2000
Description
Knockdowns of c-JUN and JUND had opposite effects on PC3 prostate cell migration. We predicted that c-JUN and JUND control the same set of cell migration genes, but in opposite directions. To test this hypothesis, mRNA with expression changes in c-JUN and JUND knockdown PC3 cell lines were compared to mRNA levels in control (luciferase knockdown) PC3 cells by RNA-seq. Overall design: mRNA profiles of luciferase knockdown (WT), c-Jun knockdown, and Jun-D knockdown in PC3 cells were generated using deep sequencing, in triplicate, using Illumina HiSeq. Knockdowns were stable shRNA expression from a lentiviral construct selected with puromycin.
Publication Title
Extracellular signal-regulated kinase signaling regulates the opposing roles of JUN family transcription factors at ETS/AP-1 sites and in cell migration.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 112 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Molecular subtypes of metastatic colorectal cancer are associated with patient response to irinotecan-based therapies.
Sample Metadata Fields
Sex, Age
View Samples- Homo sapiens
- 69 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Sporadic early onset colorectal carcinoma (EOCRC) is a growing problem that remains poorly understood. Clinical specificities and mechanisms of tumorigenesis might be relevant to both diagnosis and treatment. In this prospective study, clinicopathological features, genomic and gene expression profiles of sporadic EOCRC were compared to other well defined groups of CRC.
Publication Title
Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a morphological, molecular and genetics study.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 61 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We report that previously described molecular subtypes of colorectal cancer are associated with the response to therapy in patients with metastatic disease. We also identified a patient population with high FOLFIRI sensitivity, as indicated by their 2.7-fold longer overall survival when treated with FOLFIRI, as first-line regimen, instead of FOLFOX. Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer.
Publication Title
Molecular subtypes of metastatic colorectal cancer are associated with patient response to irinotecan-based therapies.
Sample Metadata Fields
Sex, Age
View Samples- Homo sapiens
- 51 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We report that previously described molecular subtypes of colorectal cancer are associated with the response to therapy in patients with metastatic disease. We also identified a patient population with high FOLFIRI sensitivity, as indicated by their 2.7-fold longer overall survival when treated with FOLFIRI, as first-line regimen, instead of FOLFOX. Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer.
Publication Title
Molecular subtypes of metastatic colorectal cancer are associated with patient response to irinotecan-based therapies.
Sample Metadata Fields
Sex, Age
View Samples