Promoter-bound METTL3 maintains myeloid leukaemia by m<sup>6</sup>A-dependent translation control.
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Authors
Shi, Junwei
Robson, Samuel C
Aspris, Demetrios
Migliori, Valentina
Ponstingl, Hannes
Vakoc, Christopher R
Publication Date
2017-12Journal Title
Nature
ISSN
0028-0836
Publisher
Springer Nature
Volume
552
Issue
7683
Pages
126-131
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
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Barbieri, I., Tzelepis, K., Pandolfini, L., Shi, J., Millán-Zambrano, G., Robson, S. C., Aspris, D., et al. (2017). Promoter-bound METTL3 maintains myeloid leukaemia by m<sup>6</sup>A-dependent translation control.. Nature, 552 (7683), 126-131. https://doi.org/10.1038/nature24678
Abstract
N6-methyladenosine (m6A) is an abundant internal RNA modification in both coding and non-coding RNAs, catalysed by the METTL3/METTL14 methyltransferase complex. Here we define a novel pathway specific for METTL3, implicated in the maintenance of the leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia (AML) cells in two distinct genetic screens. Down-regulation of METTL3 results in cell cycle arrest, differentiation of leukaemic cells and failure to establish leukaemia in immunodeficient mice. We show that METTL3, independently of METTL14, associates with chromatin and localizes to transcriptional start site (TSS) of active genes. The vast majority of these genes have the CAATT-box binding protein CEBPZ present at the TSS, which is required for recruitment of METTL3 to chromatin. Promoter bound METTL3 induces m6A modification within the coding region of the associated mRNA transcript, and enhances its translation by relieving ribosome stalling. We show that genes regulated by METTL3 in this way are necessary for AML. Together, these data define METTL3 as a regulator of a novel chromatin-based pathway necessary for maintenance of the leukaemic state and identify this enzyme as a novel therapeutic target for AML.
Keywords
Cell Line, Tumor, Chromatin, Ribosomes, Animals, Humans, Mice, Methyltransferases, RNA, Messenger, Adenosine, Cell Proliferation, Protein Biosynthesis, Gene Expression Regulation, Neoplastic, Transcription Initiation Site, Female, Genes, Neoplasm, Leukemia, Myeloid, Acute, Promoter Regions, Genetic, CRISPR-Cas Systems
Sponsorship
European Research Council (268569)
Kay Kendall Leukaemia Fund (KKL1103)
MRC (MC_PC_12009)
Cancer Research UK (17001)
Wellcome Trust (092096/Z/10/Z)
Cancer Research UK (23015)
Cancer Research UK (A14492)
Wellcome Trust (095663/Z/11/A)
Identifiers
External DOI: https://doi.org/10.1038/nature24678
This record's URL: https://www.repository.cam.ac.uk/handle/1810/271626
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