A novel oncogenic pathway and potential targets for CTCL. (A) IL-15 represses miR-29b levels through recruitment of Myc/Hdac-1 at the miR-29b regulatory region in CTCL cells. The decreased miR-29b releases its negative regulation on BRD4, which then binds acetylated lysine residues on chromatin at promoter and superenhancer of oncogenic genes. BRD4 regulates tumor driver genes such as NOTCH1, MYC, and RBPJ, coordinates transcriptional reprogramming, and promotes CTCL progression and drug resistance. (B) Bromodomain inhibition (via JQ1) can block dynamic transcriptional responses, remodeling the enhancers and key signaling outputs required for CTCL to progress.