Focal deletions of a promoter tether activate the IRX3 oncogene in T-cell acute lymphoblastic leukemia

• Recurrent focal deletions of a CTCF-binding site within FTO intron 8 occur in 1.5% of adult and 6.2% of pediatric patients with T-ALL.

• Focal deletions eliminate a tumor suppressor promoter tether to IRX3 enabling enhancer hijack and transcriptional activation of IRX3.

Oncogenes can be activated in cis through multiple mechanisms including enhancer hijacking events and noncoding mutations that create enhancers or promoters de 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 the FTO gene leads to aberrant expression of IRX3, an oncogene in T-cell acute lymphoblastic leukemia (T-ALL). Loss of this CTCF-bound element downstream to IRX3 (+224 kb) leads to enhancer hijack of an upstream developmentally active super-enhancer of the CRNDE long noncoding RNA (−644 kb). Unexpectedly, the CRNDE super-enhancer interacts with the IRX3 promoter with no transcriptional output until it is untethered from the FTO intronic site. We propose that “promoter tethering” of oncogenes to inert regions of the genome is a previously unappreciated biological mechanism preventing tumorigenesis.