Hoxblinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98 fusion transformed leukemia [CTCF-HiChIP-seq]

We found NUP98 fusions activate Hoxb-associated lncRNA, HoxBlinc that occupies homeotic/oncogenic topologically associated domain (TAD) boundaries in malignant hematopoiesis. Aberration of HoxBlinc led to recruitment of MLL1 complex and reorganization of homeotic/oncogenicTADs that enhanced chromatin accessibilities and aberrantly activated homeotic/hematopoietic oncogenes defined by Hoxblinc chromatin occupancies in NUP98-PHF23 related murine leukemia cells. Eliminated HoxBlinc in NUP98 fusion-driven leukemic cells resulted in loss of Hoxblinc binding, TAD integrity, recruitment of MLL complex, and MLL driven H3K4me3 and chromatin accessibility within the HoxBlinc defined domain in a CTCF independent manner, leading to inhibiting homeotic/leukemic oncogenes and mitigating NUP98 fusion-driven leukemia in xenografted mouse models. Moreover, overexpression of HoxBlinc in mouse bone marrow hematopoietic compartment developed multiple leukemia resembling NUP98-PHF23 knock-in mice via enhancing HoxBlinc binding and TAD formation to transcriptionally expanding HS/PC and myeloid/lymphoid subpopulations leading to leukemogenesis. Our studies reveal a CTCF independent role of HoxBlinc in leukemic TAD organization and oncogenic gene regulatory networks in NUP98-fusion related leukemia.