Kobayashi Yuji, Ando Koji, Imaizumi Yoshitaka, Sakamoto Hikaru, Kitanosono Hideaki, Taguchi Masataka, Mishima Hiroyuki, Kinoshita Akira, Bekytbek Shara, Baba Maki, Kato Takeharu, Horai Makiko, Itonaga Hidehiro, Sato Shinya, Yoshiura Koh-Ichiro, Miyazaki Yasushi
Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
Leuk Lymphoma. 2024 Dec;65(14):2116-2128. doi: 10.1080/10428194.2024.2393258. Epub 2024 Sep 1.
Super-enhancers (SEs) play an important role in regulating tumor-specific gene expression. JQ1, a Bromodomain-containing protein 4 (BRD4) inhibitor, exerts antitumor effects by disrupting SE-mediated regulation of gene expression. We investigated the anti-adult T-cell leukemia/lymphoma (ATL) effects of JQ1. JQ1 induced apoptosis and inhibited ATL cell proliferation. JQ1 suppressed expression through the disruption of SE-mediated gene regulation. In the previous reports, it was shown that ICs of AI-10-104 and Ro5-3335, RUNX1 inhibitors were 1-10 µM for lymphoblastic leukemia cell lines carrying mutations. In the present study, we demonstrated that ICs of AI-10-104 and Ro5-3335 were also 1-10 µM or lower for ATL cell lines. Simultaneously, AI-10-104 suppressed MYC proto-oncogene (c-MYC) expression. RUNX1 is a potential therapeutic target for ATL that promotes expression. We showed that RUNX1 expression is regulated SEs in ATL and that RUNX1 may be a novel therapeutic target for ATL.
超级增强子（SEs）在调节肿瘤特异性基因表达中发挥重要作用。JQ1是一种含溴结构域蛋白4（BRD4）抑制剂，通过破坏SE介导的基因表达调控发挥抗肿瘤作用。我们研究了JQ1对成人T细胞白血病/淋巴瘤（ATL）的抗瘤作用。JQ1诱导细胞凋亡并抑制ATL细胞增殖。JQ1通过破坏SE介导的基因调控来抑制表达。在先前的报道中，显示对于携带突变的淋巴细胞白血病细胞系，RUNX1抑制剂AI-10-104和Ro5-3335的半数抑制浓度（IC）为1-10μM。在本研究中，我们证明对于ATL细胞系，AI-10-104和Ro5-3335的IC也为1-10μM或更低。同时，AI-10-104抑制原癌基因MYC（c-MYC）的表达。RUNX1是促进表达的ATL的潜在治疗靶点。我们表明RUNX1表达在ATL中受SEs调控，并且RUNX1可能是ATL的一个新的治疗靶点。
