Small-molecule inhibitor JQ1 effect on multiple myeloma cell lines

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).