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Nucleophosmin  ( NPM1 ) is the most commonly mutated gene in acute myeloid leukemia (AML) resulting in aberrant cytoplasmic translocation of the encoded nucleolar protein (NPM1c + ). NPM1c +  maintains a unique leukemic gene expression program, characterized by activation of  HOXA / B  clusters and  MEIS1  oncogene to facilitate leukemogenesis. However, the mechanisms by which NPM1c +  controls such gene expression patterns to promote leukemogenesis remain largely unknown. Here, we show that the activation of  HOXBLINC , a  HOXB  locus-associated long non-coding RNA (lncRNA), is a critical downstream mediator of NPM1c + -associated leukemic transcription program and leukemogenesis.  HOXBLINC  loss attenuates NPM1c + -driven leukemogenesis by rectifying the signature of NPM1c +  leukemic transcription programs. Furthermore, overexpression of  HoxBlinc  ( HoxBlinc Tg) in mice enhances HSC self-renewal and expands myelopoiesis, leading to the development of AML-like disease, reminiscent of the phenotypes seen in the  Npm1  mutant knock-in ( Npm1   c/+   )  mice.  HoxBlinc Tg and  Npm1   c/+   HSPCs share significantly overlapped transcriptome and chromatin structure. Mechanistically,  HoxBlinc  binds to the promoter regions of NPM1c +  signature genes to control their activation in  HoxBlinc Tg HSPCs, via MLL1 recruitment and promoter H3K4me3 modification. Our study reveals that  HOXBLINC  lncRNA activation plays an essential oncogenic role in  NPM1c  +  leukemia . HOXBLINC  and its partner MLL1 are potential therapeutic targets for  NPM1c  +  AML.

HOXBLINC long non-coding RNA activation promotes leukemogenesis in NPM1-mutant acute myeloid leukemia