ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR293/005/SRR29306205/SRR29306205_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR293/004/SRR29306204/SRR29306204_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR293/002/SRR29306202/SRR29306202_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR293/001/SRR29306201/SRR29306201_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR293/004/SRR29306204/SRR29306204_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR293/003/SRR29306203/SRR29306203_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR293/006/SRR29306206/SRR29306206_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR293/001/SRR29306201/SRR29306201_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR293/006/SRR29306206/SRR29306206_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR293/005/SRR29306205/SRR29306205_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR293/002/SRR29306202/SRR29306202_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR293/003/SRR29306203/SRR29306203_2.fastq.gzprimaryOK200GenomicsPediatrics, Penn State College of Medicinehttps://www.ebi.ac.uk/ena/browser/view/PRJNA1120756Mus musculusxref:PubMed:39883527We 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. Overall design: We have finished the RNA-seq, ATAC-seq, ChIP-seq, ChIRP-seq, HiC-seq for WT and HoxBlinc KO in NUP98-PHF23 related leukemia cell lines and HoxBlinc Transgenic mice bone marrow cells to investigate HoxBlinc function in leukemogenesis. LK cells (Lin- Kit+) and LSK cells (Lin- Sca1+ Kit+) were sorted by FACS from the bone marrow of WT and HoxBlinc transgenic mice for single cell-RNA seq. We also used primary AML patient samples harboring NUP98-HOXA9 fusion for bulk RNA-seq.ENAfalseHoxblinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98 fusion transformed leukemia [ChIRP-seq]Hoxblinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98 fusion transformed leukemia [ChIRP-seq]2025-09-242025-02-03PRJNA1120756GSE2692241009039883527