Mice deficient of Myc super-enhancer region reveal differential control mechanism between normal and pathological growth

Abstract

The gene desert upstream of the <i>MYC</i> oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer. The region shows high conservation between human and mouse and contains multiple <i>MYC</i> enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entire <i>MYC</i> upstream super-enhancer region in mice results in 50% to 80% decrease in <i>Myc</i> expression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. These results reveal that only cells whose MYC activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer chemoprevention and therapy.