東京大学医科学研究所

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学友会セミナー

学友会セミナー:2019年3月8日

開催日時: 2019年3月8日 15:00 ~ 16:00 
開催場所: 1号館2階 2-3会議室
講師: 上久保 靖彦
所属: 京都大学大学院医学研究科人間健康科学系専攻 
ビッグデータ医科学部門・癌創薬イノベーション研究室・特定教授
演題: Potential almighty anti-cancer therapeutic strategy through CROX (Cluster regulation of RUNX family).
概要:

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 TGTGGT or TGCGGT, were highly effective against AML cells and against several poor prognosis solid tumors in a xenograft mouse models without notable adverse events. Taken together, these results identify a crucial role for the RUNX cluster in the maintenance and progression of cancers and suggest that modulation of the RUNX cluster using the PI polyamide gene-switch technology is a potential strategy to control malignancies. we refer to as “cluster regulation of RUNX (CROX).” Further studies involving clinical trials with this drug are awaited to validate the CROX strategy against human cancers.
【References】
・Accelerated leukemogenesis by truncated CBF beta-SMMHC defective in high-affinity binding with RUNX1. Kamikubo Y et al. Cancer Cell. 17:455-68, 2010.
・Genetic regulation of the RUNX transcription factor family has anti-tumor effects. Morita K ・・Kamikubo Y. J Clin Invest 127:2815-2828, 2017.
・Role of RUNX1 in hematological malignancies. Sood R*, Kamikubo Y*, et.al. Blood. 129:2070-2082, 2017.
・RUNX transcription factors potentially control E-selectin expressions in the vascular niche of mice bone marrow. Tokushige C ・・Kamikubo Y. Blood Adv. 2:509-515, 2018

世話人: 〇今井 陽一  (血液腫瘍内科)
 東條 有伸 (分子療法分野)