{{get_dataset_fail}}




{{section.text}} {{section.text}} {{section.text}} {{section.text}} {{dataset.name}}


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).

ABSTRACT: {{section.text}} {{section.text}} {{section.text}} {{section.text}} {{abstract_sections[abstract_sections.length-1].tobeReduced=='true'?"... [more]":""}} [less]

SAMPLE PROTOCOL: {{section.text}} {{section.text}} {{section.text}} {{section.text}} {{sample_protocol_sections[sample_protocol_sections.length-1].tobeReduced=='true'?"... [more]":""}} [less]

DATA PROTOCOL: {{section.text}} {{section.text}} {{section.text}} {{section.text}} {{data_protocol_sections[data_protocol_sections.length-1].tobeReduced=='true'?"... [more]":""}} [less]

REANALYSIS of: {{reanalysis_item.accession}}

REANALYZED by: {{reanalyzed_item.accession}}

OTHER RELATED OMICS DATASETS IN: {{reanalysis_item.accession}}

INSTRUMENT(S): {{instrument+';'}}

ORGANISM(S): {{organism.name + ';'}}

TISSUE(S): {{tissue+';'}}

DISEASE(S): {{disease+';'}}

SUBMITTER: {{dataset['submitter']}}

PROVIDER: {{acc}} | {{repositories[domain]}} | {{dataset['publicationDate']}}

{{publication_info[publication_index_info[dataset.publicationIds[current_publication]]].title}}

{{author.fullname.substr(0,author.fullname.length-2)}} ,

{{publication_info[publication_index_info[dataset.publicationIds[current_publication]]].citation}}


Sorry, this publication's infomation has not been loaded in the Indexer, please go directly to PUBMED or Altmetric.

ABSTRACT: {{publication_info[publication_index_info[dataset.publicationIds[current_publication]]].pub_abstract[0]}}
{{publication_info[publication_index_info[dataset.publicationIds[current_publication]]].pub_abstract[1]}} [less]

ABSTRACT: {{publication_info[publication_index_info[dataset.publicationIds[current_publication]]].pub_abstract[0]|limitTo:500}} {{publication_info[publication_index_info[dataset.publicationIds[current_publication]]].pub_abstract[0].length>500?"... [more]":""}}

Publication: {{current_publication +1}}/{{dataset.publicationIds.length}}

{{dataset.publicationIds[current_publication].publicationDate}}


Only show the datasets with similarity scores above:{{threshold}}

Threshold:
    {{threshold}}
     

The biological similarity score is calculated based on the number of molecules (Proteins, Metabolites, Genes) common between two different projects.

Similar Datasets

  • Organism: {{organism["name"]}} Not available
    {{relatedDataset['publicationDate'].substr(0,4)+"-"+relatedDataset['publicationDate'].substr(4,2)+"-"+relatedDataset['publicationDate'].substr(6,2)}}| {{relatedDataset.id}} | {{repositories[relatedDataset.source]}}