Taku Tsukamoto1, Shingo Nakahata2, Ryuichi Sato3, Akinori Kanai4, Masakazu Nakano3, Yoshiaki Chinen1, Saori Maegawa-Matsui1, Yayoi Matsumura-Kimoto1, Tomoko Takimoto-Shimomura1, Yoshimi Mizuno1, Saeko Kuwahara-Ota1, Yuka Kawaji1, Masafumi Taniwaki1,5, Toshiya Inaba4, Kei Tashiro3, Kazuhiro Morishita2, Junya Kuroda6. 1. Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan. 2. Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. 3. Department of Genomic Medical Sciences Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan. 4. Department of Molecular Oncology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. 5. Department of Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan. 6. Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan junkuro@koto.kpu-m.ac.jp.
Abstract
BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: Concomitant targeting multiple BRD4-regulated molecules may constitute a rational therapeutic strategy for MCL. Copyright
BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: Concomitant targeting multiple BRD4-regulated molecules may constitute a rational therapeutic strategy for MCL. Copyright
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