Activation of HOTTIP lncRNA perturbs HSC function leading to AML like disease

We found that posterior HOXA-associated HOTTIP lncRNA is aberrantly activated in MLL-rearranged AMLs and required for the posterior HOXA chromatin structure and gene expression. Knock-out of HOTTIP attenuates leukemic progressions of the transplanted humanized AML mice by blocking posterior HOXA-associated AML gene expression programs while the dCas-VP160 mediated reactivation of HOTTIP restores HOXA locus chromatin structure and HOXA9-A13 gene expression in the CBS7/9 boundary depleted AML cells. Finally, transgenic expression of HOTTIP lncRNA in mouse bone marrow hematopoietic cells resulted in perturbation of the balance of HSC self-renewal and differentiation and development of AML like disease by aberrant altering HOXA associated chromatin structure and transcription program. Thus, HOTTIP lncRNA acts as oncogene to reprogram leukemic associated chromatin and gene transcription. Overall design: We have finished the RNA-SEQ, ATAC-seq, ChIP-seq, CHIRP-seq, HiC-seq and whole exome-seq to investigate the role of lncRNA HOTTIP and CTCF boundaries in hematopoiesis and leukemogenesis. LSK cells (Lin- Sca1+ Kit+) were sorted by FACS from the bone marrow of WT and Hottip transgenic mice for RNA-seq, ATAC-seq assay. MOLM13 leukemia cells were used to perform the CHIRP-seq, RNA-seq, CHIP-seq and HiC-seq analysis.