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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Tzelepis, Konstantinos  ORCID logo  https://orcid.org/0000-0002-4865-7648
Shi, Junwei 
Millán-Zambrano, Gonzalo 

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.

Description

Keywords

Adenosine, Animals, CRISPR-Cas Systems, Cell Line, Tumor, Cell Proliferation, Chromatin, Female, Gene Expression Regulation, Neoplastic, Genes, Neoplasm, Humans, Leukemia, Myeloid, Acute, Methyltransferases, Mice, Promoter Regions, Genetic, Protein Biosynthesis, RNA, Messenger, Ribosomes, Transcription Initiation Site

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

552

Publisher

Springer Science and Business Media LLC
Sponsorship
European Research Council (268569)
Kay Kendall Leukaemia Fund (KKL1103)
Medical Research Council (MC_PC_12009)
Cancer Research UK (17001)
Wellcome Trust (092096/Z/10/Z)
Cancer Research UK (23015)
Cancer Research Uk (None)
Wellcome Trust (095663/Z/11/A)
Cancer Research Uk (None)