最先端研究セミナー
講演者： 上久保 靖彦 （京都大学大学院医学研究科 人間健康科学系専攻 癌創薬イノベーション研究室 准教授）
演題： A challenge to almighty anticancer agent; Anti-tumor potency of RUNX cluster regulation with “gene switch”.
日時： 7月26日（水） 12:00-13:00
会場： 発生医学研究所1階 カンファレンス室
Abstract
Runt-related transcription factor 1 (RUNX1) is generally considered to function as a tumor suppressor in the development of leukemia (1), but a growing body of evidence suggests that it has pro-oncogenic properties in acute myeloid leukemia (AML) (2)(3)(4). Here we have demonstrated that the anti-leukemic effect mediated by RUNX1 depletion is highly dependent on a functional p53-mediated cell death pathway (5). Increased expression of other RUNX family members, including RUNX2 and RUNX3, compensated for the anti-tumor effect elicited by RUNX1 silencing, and simultaneous attenuation of all RUNX family members as a cluster led to a much stronger anti-tumor effect relative to suppression of individual RUNX members. Switching off the RUNX cluster using novel 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 prognostic solid tumors in a xenograft mouse model of AML without significant notable adverse events. Taken together, this work identifies the crucial role of RUNX cluster in the maintenance and progression of cancer cells and suggests that modulation of the RUNX cluster using the PI polyamide gene switch technology may be a novel potential strategy to control malignancies.
References
- Role of RUNX1 in hematological malignancies. Kamikubo Y, Sood R, Liu P. Blood. 2017 Apr 13;129(15):2070-2082.
- Accelerated leukemogenesis by truncated CBF beta-SMMHC defective in high-affinity binding with RUNX1. Kamikubo Y, Zhao L, Wunderlich M, Corpora T, Hyde RK, Paul TA, Kundu M, Garrett L, Compton S, Huang G, Wolff L, Ito Y, Bushweller J, Mulloy JC, Liu PP. Cancer Cell. 2010 May 18;17(5):455-68.
- Cbfb/Runx1 repression-independent blockage of differentiation and accumulation of Csf2rb-expressing cells by Cbfb-MYH11. Hyde RK, Kamikubo Y, Anderson S, Kirby M, Alemu L, Zhao L, Liu PP. Blood. 2010 Feb 18;115(7):1433-43.
- The C-terminus of CBFβ-SMMHC is required to induce embryonic hematopoietic defects and leukemogenesis. Kamikubo Y, Hyde RK, Zhao L, Alemu L, Rivas C, Garrett LJ, Liu PP. Blood. 2013 Jan 24;121(4):638-42.
- Genetic regulation of the RUNX transcription factor family has anti-tumor effects Morita K, Suzuki K, Maeda S, Matsuo A, Mitsuda Y, Tokushige C, Kashiwazaki G, Taniguchi J, Maeda R, Noura M, Hirata M, Kataoka T, Yano A, Yamada Y, Kiyose H, Tokumasu M, Matsuo H, Tanaka S, Okuno Y, Muto M, Naka K, Ito K, Kitamura T, Kaneda Y, Liu P.P, Bando T, Adachi S, Sugiyama H and Kamikubo Y. Journal of Clinical Investigation In press.
担当分野： IRCMS 馬場（内線：6836）
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