Genetic regulation of the RUNX transcription factor family has antitumor effects
| Autor: | Chieko Tokushige, Shintaro Maeda, Masahiro Hirata, Akihiko Matsuo, Ayaka Yano, Toshikazu Bando, Paul P. Liu, Sunao Tanaka, Kosei Ito, Tatsuki R. Kataoka, Hiroki Kiyose, Mayu Tokumasu, Hidemasa Matsuo, Mina Noura, Gengo Kashiwazaki, Yasuhiko Kamikubo, Ken Morita, Manabu Muto, Yasufumi Kaneda, Yasushi Okuno, Kazuhito Naka, Rina Maeda, Yoshimi Yamada, Yoshihide Mitsuda, Kensho Suzuki, Hiroshi Sugiyama, Junichi Taniguchi, Souichi Adachi, Toshio Kitamura |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Myeloid Biology Mice 03 medical and health sciences chemistry.chemical_compound Mice Inbred NOD Cell Line Tumor hemic and lymphatic diseases medicine Animals Humans Gene silencing Pyrroles Antineoplastic Agents Alkylating Transcription factor Core Binding Factor alpha Subunits Myeloid leukemia General Medicine medicine.disease Xenograft Model Antitumor Assays RUNX2 Leukemia Myeloid Acute Nylons Leukemia 030104 developmental biology medicine.anatomical_structure RUNX1 chemistry Cancer cell Cancer research Tumor Suppressor Protein p53 Research Article |
| Zdroj: | Journal of Clinical Investigation. 127:2815-2828 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci91788 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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