期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-22095-2
关键词
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资金
- National Institute of Health [R01HL141950, R01CA172408, R00CA178191, R01DK121831, R01DK110108]
- Cancer Prevention AMP
- Research Institute of Texas [CPRIT RP200242]
- Florida Academic Cancer Center Alliance (FACCA) Award
Mutations in the nucleophosmin (NPM1) gene lead to a specific gene expression program that causes acute myeloid leukemia. The activation of a long non-coding RNA associated with the HOXB locus by mutant NPM1 is crucial for its oncogenic transcriptional program and leukemia development.
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 (HoxBlincTg) 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. HoxBlincTg 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 HoxBlincTg 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. Nucleophosmin (NPM1) gene mutation induces a specific gene expression program leading to acute myeloid leukaemia. Here, the authors show that mutant NPM1 activates a HOXB locus-associated long non-coding RNA which is essential for its associated oncogenic transcriptional program and leukaemia development.
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