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

Ganqian Zhu, Huacheng Luo, Yang Feng, Olga A. Guryanova, Jianfeng Xu, Shi Chen, Qian Lai, Arati Sharma, Bing Xu, Zhigang Zhao, Ru Feng, Hongyu Ni, David Claxton, Ying Guo, Ruben A. Mesa, Yi Qiu, Feng-Chun Yang, Wei Li, Stephen D. Nimer, Suming Huang () and Mingjiang Xu ()
Additional contact information
Ganqian Zhu: University of Texas Health San Antonio
Huacheng Luo: Pennsylvania State University College of Medicine
Yang Feng: University of Florida College of Medicine
Olga A. Guryanova: University of Florida College of Medicine
Jianfeng Xu: Dan L. Duncan Cancer Center, Baylor College of Medicine
Shi Chen: University of Texas Health San Antonio
Qian Lai: Pennsylvania State University College of Medicine
Arati Sharma: Pennsylvania State University College of Medicine
Bing Xu: The First Affiliated Hospital of Xiamen University
Zhigang Zhao: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy
Ru Feng: Southern Medical University
Hongyu Ni: Wayne State University School of Medicine
David Claxton: Pennsylvania State University College of Medicine
Ying Guo: University of Miami Miller School of Medicine
Ruben A. Mesa: University of Texas Health San Antonio
Yi Qiu: Pennsylvania State University College of Medicine
Feng-Chun Yang: University of Miami Miller School of Medicine
Wei Li: University of California
Stephen D. Nimer: University of Miami Miller School of Medicine
Suming Huang: Pennsylvania State University College of Medicine
Mingjiang Xu: University of Texas Health San Antonio

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract 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 (Npm1c/+) mice. HoxBlincTg and Npm1c/+ 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.

Date: 2021
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DOI: 10.1038/s41467-021-22095-2

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