 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Feb 25, 2013 |
| Title |
Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
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.
|
| |
|
| Overall design |
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).
|
| |
|
| Contributor(s) |
Stegmaier K |
| Citation(s) |
23430699 |
| |
| Submission date |
Jan 09, 2013 |
| Last update date |
Aug 23, 2018 |
| Contact name |
Gabriela Alexe |
| E-mail(s) |
[email protected]
|
| Organization name |
Broad Institute
|
| Department |
Computational Biology and Bioinformatics
|
| Street address |
415 Main St.
|
| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02142 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL15207 |
[PrimeView] Affymetrix Human Gene Expression Array |
|
| Samples (12)
|
|
| Relations |
| BioProject |
PRJNA185813 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE43392_RAW.tar |
23.7 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
|
|
|
|
 |
Less...
More...