Alternative Title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
Degree grantor/typeNagasaki University (長崎大学)
Note (General)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)
http://hdl.handle.net/10069/00041989
Collection (particular)国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文
Date Accepted (W3CDTF)2023-03-07T16:07:51+09:00
Data Provider (Database)国立国会図書館 : 国立国会図書館デジタルコレクション