N6-methyladenosine (m6A) is an abundant internal RNA modification in both coding1 29 and non-coding RNAs2,3, catalysed by the METTL3/METTL14 methyltransferase complex4 30 . 31 Here we define a novel pathway specific for METTL3, implicated in the maintenance of the 32 leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid 33 leukaemia (AML) cells in two distinct genetic screens. Down-regulation of METTL3 results 34 in cell cycle arrest, differentiation of leukaemic cells and failure to establish leukaemia in 35 immunodeficient mice. We show that METTL3, independently of METTL14, associates 36 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 TSS5 37 , 38 which is required for recruitment of METTL3 to chromatin. Promoter bound METTL3 39 induces m6A modification within the coding region of the associated mRNA transcript, and 40 enhances its translation by relieving ribosome stalling. We show that genes regulated by 41 METTL3 in this way are necessary for AML. Together, these data define METTL3 as a 42 regulator of a novel chromatin-based pathway necessary for maintenance of the leukaemic 43 state and identify this enzyme as a novel therapeutic target for AML.