Focal Deletions of a Promoter Tether Activate theIRX3Oncogene in T Cell Acute Lymphoblastic Leukemia

Abstract

Oncogenes can be activated incisthrough multiple mechanisms including enhancer hijacking events and noncoding mutations that create enhancers or promotersde novo. These paradigms have helped parse somatic variation of noncoding cancer genomes, thereby providing a rationale to identify noncanonical mechanisms of gene activation. Here we describe a novel mechanism of oncogene activation whereby focal copy number loss of an intronic element within theFTOgene leads to aberrant expression ofIRX3, an oncogene in T cell acute lymphoblastic leukemia (T-ALL). Loss of this CTCF bound element downstream toIRX3(+224 kb) leads to enhancer hijack of an upstream developmentally active super-enhancer of theCRNDElong noncoding RNA (-644 kb). Unexpectedly, theCRNDEsuper-enhancer interacts with theIRX3promoter with no transcriptional output until it is untethered from theFTOintronic site. We propose that ‘promoter tethering’ of oncogenes to inert regions of the genome is a previously unappreciated biological mechanism preventing tumorigenesis.