Promoter-bound METTL3 maintains myeloid leukaemia by m(6)A-dependent translation control

Barbieri, I., Tzelepis, K., Pandolfini, L., Shi, J., Millan-Zambrano, G., Robson, S. C., Aspris, D., Migliori, V., Bannister, A. J., Han, N., De Braekeleer, E., Ponstingl, H., Hendrick, A., Vakoc, C. R., Vassiliou, G. S., Kouzarides, T. (December 2017) Promoter-bound METTL3 maintains myeloid leukaemia by m(6)A-dependent translation control. Nature, 552 (7683). pp. 126-131. ISSN 0028-0836

URL: https://www.ncbi.nlm.nih.gov/pubmed/29186125
DOI: 10.1038/nature24678

Abstract

N(6)-methyladenosine (m(6)A) 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 m(6)A 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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Chromatin dynamics
diseases & disorders > cancer > cancer types > leukemia
CSHL Authors:
Communities: CSHL labs > Vakoc lab
CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
Depositing User: Matt Covey
Date: 7 December 2017
Date Deposited: 08 Dec 2017 17:41
Last Modified: 12 Jun 2018 19:28
Related URLs:
URI: http://repository.cshl.edu/id/eprint/35707

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