HoxBlinc depletion in NUP98 fusion–driven leukemia impaired HoxBlinc binding, TAD integrity, MLL1 recruitment, and the MLL1-driven chromatin signature within HoxBlinc-defined TADs in a CCCTC-binding factor–independent (CTCF-independent) manner, leading to inhibited homeotic/leukemic oncogenes that mitigated NUP98 fusion–driven leukemogenesis in xenografted mouse models. Here, NUP98 is linked to leukemia.