イベント&セミナー

[発生研セミナー] 1/24 11:00~ 京都大 上久保靖彦先生

2019.01.23 ●セミナー

352nd IMEG Seminar

 

 

【Date】Jan. 24 (Thu), 2019 11:00~12:00
【Venue】Conference room, 1st floor,
Institute of Molecular Embryology and Genetics (IMEG),
Kumamoto University

 

【Title】 Cluster regulation of transcription factors with “gene switch”

 

【Speaker】 Yasuhiko Kamikubo, M.D.,PhD., Professor.
Biomedical Data Intelligence, Department of Human Health Sciences,
Graduate School of Medicine, Kyoto University

 

 

【Abstract】
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 anti-leukemic 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 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 etc.

 

【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.
・The C-terminus of CBFβ-SMMHC is required to induce embryonic hematopoietic defects and leukemogenesis. Kamikubo Y et al. Blood. 121:638-642, 2013.
・Genetic regulation of the RUNX transcription factor family has anti-tumor effects. Morita K et al. J Clin Invest 127:2815-2828, 2017.
・Role of RUNX1 in hematological malignancies. Kamikubo Y*, Sood R* et.al. Blood. 129:2070-2082, 2017.
Paradoxical enhancement of leukemogenesis in acute myeloid leukemia with moderately-attenuated RUNX1 expressions. Morita K et.al. Blood Adv. 1:1440-1451, 2017.
・RUNX transcription factors potentially control E-selectin expressions in the vascular niche of mice bone marrow. Tokushige C et.al Blood Adv. 2:509-515, 2018.
・Genetic compensation of RUNX family transcription factors in leukemia. Kamikubo Y Cancer Sci. 2018. doi: 10.1111/cas.13664.

 

【Contact】Dept. of Kidney Development, Ryuichi Nishinakamura (Ext. 6615)

 

このセミナーは「発生医学の共同研究拠点」の一環として行われます。