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

作者：Zhu, Ganqian; Luo, Huacheng; Feng, Yang; Guryanova, Olga A.; Xu, Jianfeng; Chen, Shi; Lai, Qian; Sharma, Arati; Xu, Bing; Zhao, Zhigang; Feng, Ru; Ni, Hongyu; Claxton, David; Guo, Ying; Mesa, Ruben A.; Qiu, Yi; Yang, Feng-Chun; Li, Wei; Nimer, Stephen D.; Huang, Suming^*; Xu, Mingjiang^*

来源：Nature Communications, 2021, 12(1): 1956.

DOI：10.1038/s41467-021-22095-2

• CYTOPLASMIC NUCLEOPHOSMIN
• EXPRESSION PATTERNS
• READ ALIGNMENT
• GENE
• CHROMATIN
• MUTATIONS
• MECHANISMS
• MAINTAINS
• TOPHAT
• AML

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.

• 单位
  南方医科大学; 1; 厦门大学