Promoter-bound METTL3 maintains myeloid leukemia by m6A-dependent regulation of protein translation

N6-methyladenosine (m6A) is an abundant internal RNA modification, in both coding and non-coding RNAs, catalyzed by the METTL3/METTL14 methyltransferase complex. We identified METTL3 as an essential gene for acute myeloid leukemia (AML) cell growth in two distinct genetic screens. Down-regulation of METTL3 results in cell cycle arrest, differentiation of leukemic cells and failure to establish leukemia in immunodeficient mice. We show that METTL3, independently of METTL14, associates with chromatin and localizes to the transcriptional start site (TSS) of 83 active genes. The vast majority of these genes have a CAATT-box motif at their TSS, are occupied by a specific set of transcription factors including NFY, WDR5, KLF9 and they harbor specific histone modifications (e.g. H3R2me2s). Promoter bound METTL3 induces m6A modification within the coding region of the associated mRNA transcript and it enhances translation due to relief of ribosome stalling. We show that genes regulated by METTL3 in this way are necessary for AML-leukemia. Together, these data define a new mechanism of gene regulation by METTL3 and identify this enzyme as a novel therapeutic target for AML.