Morita Ken, Suzuki Kensho, Maeda Shintaro, Matsuo Akihiko, Mitsuda Yoshihide, Tokushige Chieko, Kashiwazaki Gengo, Taniguchi Junichi, Maeda Rina, Noura Mina, Hirata Masahiro, Kataoka Tatsuki, Yano Ayaka, Yamada Yoshimi, Kiyose Hiroki, Tokumasu Mayu, Matsuo Hidemasa, Tanaka Sunao, Okuno Yasushi, Muto Manabu, Naka Kazuhito, Ito Kosei, Kitamura Toshio, Kaneda Yasufumi, Liu Paul P, Bando Toshikazu, Adachi Souichi, Sugiyama Hiroshi, Kamikubo Yasuhiko
Department of Human Health Sciences, Graduate School of Medicine.
Department of Pediatrics, Graduate School of Medicine, and.
J Clin Invest. 2017 Jun 30;127(7):2815-2828. doi: 10.1172/JCI91788. Epub 2017 May 22.
Runt-related transcription factor 1 (RUNX1) is generally considered to function as a tumor suppressor in the development of leukemia, but a growing body of evidence suggests that it has pro-oncogenic properties in acute myeloid leukemia (AML). Here we have demonstrated that the antileukemic effect mediated by RUNX1 depletion is highly dependent on a functional p53-mediated cell death pathway. Increased expression of other RUNX family members, including RUNX2 and RUNX3, compensated for the antitumor effect elicited by RUNX1 silencing, and simultaneous attenuation of all RUNX family members as a cluster led to a much stronger antitumor effect relative to suppression of individual RUNX members. Switching off the RUNX cluster using alkylating agent-conjugated pyrrole-imidazole (PI) polyamides, which were designed to specifically bind to consensus RUNX-binding sequences, was highly effective against AML cells and against several poor-prognosis solid tumors in a xenograft mouse model of AML without notable adverse events. Taken together, these results identify a crucial role for the RUNX cluster in the maintenance and progression of cancer cells and suggest that modulation of the RUNX cluster using the PI polyamide gene-switch technology is a potential strategy to control malignancies.
runt相关转录因子1（RUNX1）通常被认为在白血病发展过程中起肿瘤抑制作用，但越来越多的证据表明，它在急性髓系白血病（AML）中具有促癌特性。在这里，我们已经证明，RUNX1缺失介导的抗白血病作用高度依赖于功能性p53介导的细胞死亡途径。包括RUNX2和RUNX3在内的其他RUNX家族成员的表达增加，补偿了RUNX1沉默所引发的抗肿瘤作用，并且作为一个簇同时减弱所有RUNX家族成员相对于抑制单个RUNX成员导致更强的抗肿瘤作用。使用设计用于特异性结合共有RUNX结合序列的烷基化剂共轭吡咯-咪唑（PI）聚酰胺关闭RUNX簇，在AML异种移植小鼠模型中对AML细胞和几种预后不良的实体瘤非常有效，且没有明显的不良事件。综上所述，这些结果确定了RUNX簇在癌细胞维持和进展中的关键作用，并表明使用PI聚酰胺基因开关技术调节RUNX簇是控制恶性肿瘤的潜在策略。
