Gene expression study in Neuroblastoma after BET inhibition
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Gopinath Ganji
PROVIDER: E-GEOD-47386 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Microarray-based genome-wide measurements of copy number alterations and of transcriptome variations are proposed for neuroblastoma prognosis and possible treatment choice. Nonetheless, they lack to provide clues on a neglected layer of systems-level changes, the translatome, whose variations are defined by the activity of the translational regulatory machinery. Our study extends the conventional genome-wide approaches to translatome profiling in neuroblastoma, by means of polysomal sucrose gradient separation followed by microarray analysis. The panel of fourteen parental (not subcloned) neuroblastoma cell lines used in the study includes: CHP-134, SIMA, NB-69, LAN-1, KELLY, CHP-126, CHP-212, SK-N-BE(2), IMR-32, SK-N-AS, SK-N-SH, STA-NB-7, STA-NB-1, STA-NB-10 cells. Each cell line has been profiled with high resolution array CGH analysis for copy number changes, and for transcriptome and translatome variations. The integration of these three types of data sets obtained from the same cells can provide information on the impact in neuroblastoma of a defined pattern of genomic lesions on both transcriptional and translational alterations of gene expression.
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Project description:The aim of the project was to determine the expression profiles of murine Myc-driven lymphpma cells (Lambda-820) treated with vehicle (DMSO, 1:1000), a BET inhibitor (RVX2135), an ATR inhibitor (VE-821) or a combination of RVX2135 and VE-821. All experimnets were performed in presence of 10uM Q-VD-OPH to block apoptosis. Cells were harvested 24 h after treatment start. 4 samples (DMSO, RVX2135, VE-821 or RVX2135/VE-821) in duplicates
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Project description:Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically-defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis demonstrated downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knock-down phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in three in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma. Significance: Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anti-cancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, demonstrate a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma. JQ1 is a novel thieno-triazolo-1,4-diazepine, which displaces BET bromodomains from chromatin by competitively binding to the acetyl lysine recognition pocket. BE(2)-C and Kelly cells were treated in triplicate with 1 µM JQ1 or DMSO for 24 hours. RNA was extracted and a decrease in MYCN transcript was confirmed by real time RT-PCR as described above. The samples were profiled using the Affymetrix PrimeView Human Gene Expression Array (Affymetrix) at Beth Israel Deaconess Medical Center (Boston, MA, USA).
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