Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression analysis of B-ALL cells treated with BET inhibitor

ABSTRACT: Two human acute lymphoblastic leukemia cell lines were treated with a BET bromodomain inhibitor that blocks BET association with chromatin. These cell lines, MHH-CALL4 and MUTZ-5, each carry translocation of the CRLF2 gene into the IgH locus, and their growth was found to be susceptible to BET inhibition. Gene expression changes were analyzed in each cell line versus vehicle control. Cell were treated for 8 hours with either DMSO or 500nM of the BET bromodomain inhbitor JQ1. Three samples for each treatment were taken and analyzed for each cell line. CEL files were analyzed at both the core and extended gene level by RMA with the Affymetrix Expression Console software.

ORGANISM(S): Homo sapiens

SUBMITTER: Christopher Ott

PROVIDER: E-GEOD-39995 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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 ÂµM 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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Gene expression analysis of B-ALL cells treated with BET inhibitor

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