RRC ID 49234
Author 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 PP, Bando T, Adachi S, Sugiyama H, Kamikubo Y.
Title Genetic regulation of the RUNX transcription factor family has antitumor effects.
Journal J. Clin. Invest.
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 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.
Volume 127(7)
Pages 2815-2828
Published 2017-6-30
DOI 10.1172/JCI91788
PII 91788
PMID 28530640
PMC PMC5490777
MeSH Animals Antineoplastic Agents, Alkylating / chemistry Antineoplastic Agents, Alkylating / pharmacology* Cell Line, Tumor Core Binding Factor alpha Subunits* / genetics Core Binding Factor alpha Subunits* / metabolism Humans Leukemia, Myeloid, Acute* / drug therapy Leukemia, Myeloid, Acute* / genetics Leukemia, Myeloid, Acute* / metabolism Mice Mice, Inbred NOD Nylons / chemistry Nylons / pharmacology Pyrroles / chemistry Pyrroles / pharmacology Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism* Xenograft Model Antitumor Assays
IF 13.251
Times Cited 0
WOS Category MEDICINE, RESEARCH & EXPERIMENTAL
Resource
DNA material CS-RfA-ETV (RDB08020) CS-RfA-ETR (RDB08362) CSII-EF-MCS-IRES2-hKO1 (RDB07915) CSII-EF-MCS-IRES2-Venus (RDB04384) CS-RfA-ETBsd (RDB07917) pENTR4-H1tetOx1 (RDB07916).