Genetic regulation of the RUNX transcription factor family has antitumor effects

The Journal of Clinical Investigation
Ken MoritaYasuhiko Kamikubo

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 techno...Continue Reading

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Citations

Dec 2, 2017·Scientific Reports·Ken MoritaYasuhiko Kamikubo
Jun 9, 2018·Cancer Science·Yasuhiko Kamikubo
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Datasets Mentioned

BETA
GSE94835

Methods Mentioned

BETA
acetylation
reverse transcription PCR
immunoprecipitation
xenograft
PCR
nuclear magnetic resonance
NMR

Software Mentioned

RefExA
Image Lab
Gene set enrichment analysis ( GSEA )
COMPUSYN
Database for Annotation , Visualization and Integrated Discove...

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