BRD4-Regulated Molecular Targets in Mantle Cell Lymphoma: Insights into Targeted Therapeutic Approach

• Published in: Cancer genomics & proteomics Vol. 17; no. 1; pp. 77 - 89
• Main Authors: TSUKAMOTO, TAKU, NAKAHATA, SHINGO, SATO, RYUICHI, KANAI, AKINORI, NAKANO, MASAKAZU, CHINEN, YOSHIAKI, MAEGAWA-MATSUI, SAORI, MATSUMURA-KIMOTO, YAYOI, TAKIMOTO-SHIMOMURA, TOMOKO, MIZUNO, YOSHIMI, KUWAHARA-OTA, SAEKO, KAWAJI, YUKA, TANIWAKI, MASAFUMI, INABA, TOSHIYA, TASHIRO, KEI, MORISHITA, KAZUHIRO, KURODA, JUNYA
• Format: Journal Article
• Language: English
• Published: Greece International Institute of Anticancer Research 01.01.2020
• Subjects: Anticancer properties; Antitumor activity; B-cell receptor; BLNK protein; Cell proliferation; Chromatin; Gene expression; Gene sequencing; Genes; Ikaros protein; Immunoprecipitation; Lymphocytes B; Lymphoma; Mantle; Mantle cell lymphoma; Pax5 protein; Signal transduction; Therapeutic applications; Transcription; Zinc; Zinc finger proteins; ChIP-Seq; drug resistance; super-enhancer; Mantle cell lymphoma; BRD4
• ISSN: 1109-6535; 1790-6245
• DOI: 10.21873/cgp.20169

Since bromodomain-containing protein 4 (BRD4) facilitates the transcription of genes important for neoplastic cells in a cancer-type specific manner, BRD4-regulated molecules may also include therapeutic targets for mantle cell lymphoma (MCL), a treatment-refractory subtype of malignant lymphoma. In order to uncover direct BRD4-regulated targets in MCL, we performed integrated analysis using the pathway database and the results of both gene-expression profiling and chromatin immunoprecipitation with parallel sequencing for BRD4. Treatment with BRD4 inhibitor I-BET151 exerted a dose-dependent inhibitory effect on cell proliferation in MCL cell lines. BRD4 was found to directly regulate series of genes involved in the B-cell receptor (BCR) signaling pathway, including B-cell linker (BLNK), paired box 5 (PAX5), and IKAROS family zinc finger 3 (IKZF3), and several oncogenes, such as MYB. Indeed, the combinatory inhibition of BCR pathway and IKZF showed an additive antitumor effect. Concomitant targeting multiple BRD4-regulated molecules may constitute a rational therapeutic strategy for MCL.