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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Carcinogenesis / genetics*
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Carcinogenesis / metabolism
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Carcinogenesis / pathology
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Cell Line, Tumor
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Cell Proliferation
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Gene Expression Profiling
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Gene Expression Regulation, Leukemic*
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Heterografts
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / metabolism
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Histones / genetics
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Histones / metabolism
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Homeodomain Proteins / genetics*
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Homeodomain Proteins / metabolism
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Humans
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology
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Mice
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Mice, Transgenic
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Multigene Family
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Mutation
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Myeloid Ecotropic Viral Integration Site 1 Protein / genetics
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Myeloid Ecotropic Viral Integration Site 1 Protein / metabolism
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Myeloid-Lymphoid Leukemia Protein / genetics
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Myeloid-Lymphoid Leukemia Protein / metabolism
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Myelopoiesis / genetics
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics*
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Nucleophosmin
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Promoter Regions, Genetic
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RNA, Long Noncoding / agonists
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RNA, Long Noncoding / genetics*
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RNA, Long Noncoding / metabolism
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Signal Transduction
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Transcription, Genetic
Substances
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Histones
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Homeodomain Proteins
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KMT2A protein, human
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MEIS1 protein, human
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Myeloid Ecotropic Viral Integration Site 1 Protein
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NPM1 protein, human
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Npm1 protein, mouse
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Nuclear Proteins
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RNA, Long Noncoding
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histone H3 trimethyl Lys4
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Nucleophosmin
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Myeloid-Lymphoid Leukemia Protein
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Histone-Lysine N-Methyltransferase