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Nature. 2017 Dec 7;552(7683):126-131. doi: 10.1038/nature24678. Epub 2017 Nov 27.

Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control.

Author information

1
The Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
2
Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
3
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
4
Storm Therapeutics Ltd, Moneta Building (B280), Babraham Research Campus, Cambridge CB22 3AT, UK.
5
Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK.
6
Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK.

Abstract

N6-methyladenosine (m6A) is an abundant internal RNA modification in both coding and non-coding RNAs that is catalysed by the METTL3-METTL14 methyltransferase complex. However, the specific role of these enzymes in cancer is still largely unknown. Here we define a pathway that is specific for METTL3 and is implicated in the maintenance of a leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia cells in two distinct genetic screens. Downregulation 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 the transcriptional start sites of active genes. The vast majority of these genes have the CAATT-box binding protein CEBPZ present at the transcriptional start site, and this 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 acute myeloid leukaemia. Together, these data define METTL3 as a regulator of a chromatin-based pathway that is necessary for maintenance of the leukaemic state and identify this enzyme as a potential therapeutic target for acute myeloid leukaemia.

PMID:
29186125
PMCID:
PMC6217924
DOI:
10.1038/nature24678
[Indexed for MEDLINE]
Free PMC Article

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