HoxBlinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98-rearranged leukemia.

Although nucleoporin 98 (NUP98) fusion oncogenes often drive aggressive pediatric leukemia by altering chromatin structure and expression of homeobox (HOX) genes, underlying mechanisms remain elusive. Here, we report that the Hoxb-associated lncRNA HoxBlinc was aberrantly activated in NUP98-PHF23 fusion-driven leukemias. HoxBlinc chromatin occupancies led to elevated mixed-lineage leukemia 1 (MLL1) recruitment and aberrant homeotic topologically associated domains (TADs) that enhanced chromatin accessibilities and activated homeotic/hematopoietic oncogenes. 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. Mechanistically, HoxBlinc overexpression in the mouse hematopoietic compartment induced leukemias resembling those in NUP98-PHF23-knockin (KI) mice via enhancement of HoxBlinc chromatin binding, TAD formation, and Hox gene aberration, leading to expansion of hematopoietic stem and progenitor cell and myeloid/lymphoid cell subpopulations. Thus, our studies reveal a CTCF-independent role of HoxBlinc in leukemic TAD organization and oncogene-regulatory networks.