Proposed mechanism of IRX3 oncogenic activation in T-ALL due to the loss of a “promoter tether.” IRX3 resides in a TAD that contains 2 relevant regulatory elements: 1 within intron 8 of FTO and 1 within CRNDE. In cells with wild-type FTO (left panel), the IRX3 promoter is sequestered to a relatively inert region of FTO intron 8, yielding minimal transcriptional activity. This trapping is facilitated by CTCF binding at the FTO intron, which creates an IRX3 “promoter tether.” In T-ALL cells with focal deletions of FTO intron 8 (right panel), the loss of CTCF binding unleashes the IRX3 promoter, allowing it to be hijacked by the distal highly active developmental superenhancer of CRNDE, resulting in oncogenic IRX3 transcription.