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

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.