Unknown,Transcriptomics,Genomics,Proteomics

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Small-molecule inhibitor JQ1 effect on multiple myeloma cell lines

ABSTRACT: Pathologic activation of c-Myc plays a central role in pathogenesis of several neoplasias, including multiple myeloma. However, therapeutic targeting of c-Myc has remained elusive due to its lack of a clear ligand-binding domain. We therefore targeted c-Myc transcriptional function by another means, namely the disruption of chromatin-dependent signal transduction. Members of the bromodomain and extra-terminal (BET) subfamily of human bromodomain proteins (BRD2, BRD3 and BRD4) associate with acetylated chromatin and facilitate transcriptional activation by increasing the effective molarity of recruited transcriptional activators. Notably, BRD4 marks select M/G1 genes in mitotic chromatin for transcriptional memory and direct post-mitotic transcription, via direct interaction with the positive transcription elongation factor complex b (P-TEFb). Because c-Myc is known to regulate promoter-proximal pause release of Pol II, also through the recruitment of P-TEFb, we evaluated the selective small-molecule inhibitor of BET bromodomains, JQ1, as a chemical probe to interrogate the role of BET bromodomains in Myc-dependent transcription and to explore their role as therapeutic targets in c-Myc-driven neoplasias. Duplicate cultures of MM.1S, OPM1 and KMS11 human myeloma cells were treated with either DMSO alone or with JQ1 (500 nM), for 24 hours. Total RNA was extracted and hybridized to Affymetrix human Gene 1.0 ST microarrays (two arrays per treatment per cell line for a total of 12 arrays).

ORGANISM(S): Homo sapiens

SUBMITTER: Madeleine Lemieux

PROVIDER: E-GEOD-31365 | 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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Small-molecule inhibitor JQ1 effect on multiple myeloma cell lines

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