HOXBLINC long non-coding RNA activation promotes leukemogenesis in NPM1-mutant acute myeloid leukemia
| Autor: | Qian Lai, Hongyu Ni, Shi Chen, Ying Guo, Huacheng Luo, Yi Qiu, Feng Chun Yang, David F. Claxton, Ganqian Zhu, Yang Feng, Suming Huang, Ru Feng, Jianfeng Xu, Bing Xu, Olga A. Guryanova, Stephen D. Nimer, Arati Sharma, Zhigang Zhao, Ruben A. Mesa, Wei Li, Mingjiang Xu |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Transcription Genetic Carcinogenesis General Physics and Astronomy Histones Mice 0302 clinical medicine Transcription (biology) hemic and lymphatic diseases Gene expression Myeloid Ecotropic Viral Integration Site 1 Protein Promoter Regions Genetic Regulation of gene expression Myelopoiesis Multidisciplinary Chemistry Gene Expression Regulation Leukemic Myeloid leukemia Nuclear Proteins Chromatin Cell biology Stem-cell research Leukemia Leukemia Myeloid Acute 030220 oncology & carcinogenesis Multigene Family Self-renewal Heterografts RNA Long Noncoding Nucleophosmin Myeloid-Lymphoid Leukemia Protein Signal Transduction NPM1 Science Mice Transgenic General Biochemistry Genetics and Molecular Biology Article Acute myeloid leukaemia 03 medical and health sciences Cell Line Tumor medicine Animals Humans Cancer models Cell Proliferation Homeodomain Proteins Gene Expression Profiling General Chemistry Histone-Lysine N-Methyltransferase medicine.disease 030104 developmental biology Mutation |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-17 (2021) |
| ISSN: | 2041-1723 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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