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

Isaia Barbieri, Konstantinos Tzelepis, Luca Pandolfini, Junwei Shi, Gonzalo Millán-zambrano, Samuel C. Robson, Demetrios Aspris, Valentina Migliori, Andrew J. Bannister, Namshik Han, Etienne De Braekeleer, Hannes Ponstingl, Alan Hendrick, Christopher R. Vakoc, George S. Vassiliou, Tony Kouzarides

Research output: Contribution to journalArticlepeer-review

79 Downloads (Pure)

Abstract

N6-methyladenosine (m6A) is an abundant internal RNA modification in both coding1 and non-coding RNAs2,3 that is catalysed by the METTL3–METTL14 methyltransferase complex4. 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 site5, 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.
Original languageEnglish
Pages (from-to)126-131
Number of pages6
JournalNature
Volume552
Early online date27 Nov 2017
DOIs
Publication statusPublished - 7 Dec 2017
Externally publishedYes

Fingerprint

Dive into the research topics of 'Promoter-bound METTL3 maintains myeloid leukaemia by m<sup>6</sup>A-dependent translation control'. Together they form a unique fingerprint.

Cite this