並列タイトル等アルボシジブはスーパーエンハンサーを介してIRF4発現を抑制し、成人T細胞白血病・リンパ腫の細胞増殖を抑制する
授与機関名Nagasaki University (長崎大学)
一般注記Adult T-cell leukemia/lymphoma (ATL) is an intractable hematological malignancy with extremely poor prognosis. Recent studies have revealed that super-enhancers (SE) play important roles in controlling tumor-specific gene expression and are potential therapeutic targets for neoplastic diseases including ATL. Cyclin-dependent protein kinase (CDK) 9 is a component of a complex comprising transcription factors (TFs) that bind the SE region. Alvocidib is a CDK9 inhibitor that exerts antitumor activity by inhibiting RNA polymerase (Pol) II phosphorylation and suppressing SE-mediated, tumor-specific gene expression. The present study demonstrated that alvocidib inhibited the proliferation of ATL cell lines and tumor cells from patients with ATL. RNA sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) disclosed that SE regulated IRF4 in the ATL cell lines. Previous studies showed that IRF4 suppression inhibited ATL cell proliferation. Hence, IRF4 is a putative alvocidib target in ATL therapy. The present study revealed that SE-mediated IRF4 downregulation is a possible mechanism by which alvocidib inhibits ATL proliferation. Alvocidib also suppressed ATL in a mouse xenograft model. Hence, the present work demonstrated that alvocidib has therapeutic efficacy against ATL and partially elucidated its mode of action. It also showed that alvocidib is promising for the clinical treatment of ATL and perhaps other malignancies and neoplasms as well.
長崎大学学位論文 学位記番号:博(医歯薬)甲第1482号 学位授与年月日:令和4年12月7日
Author: Hikaru Sakamoto, Koji Ando, Yoshitaka Imaizumi, Hiroyuki Mishima, Akira Kinoshita, Yuji Kobayashi, Hideaki Kitanosono, Takeharu Kato, Yasushi Sawayama, Shinya Sato, Tomoko Hata, Masahiro Nakashima, Koh-Ichiro Yoshiura, Yasushi Miyazaki
Citation: Cancer Science, 113(12), pp. 4092-4103; 2022
identifier:Nagasaki University (長崎大学), 博士(医学) (2022-12-07)
著作権情報© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
関連情報http://hdl.handle.net/10069/00041989
連携機関・データベース国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）