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

The methyltransferase METTL3 promotes the leukaemic state in acute myeloid leukaemia (AML) by catalysing the m6A RNA modification through its recruitment on the transcription start sites of AML-associated genes. N6-methyladenosine (m6A) is an RNA modification in coding and non-coding RNAs that is catalysed by the METTL3–METTL14 methyltransferase complex and affects various aspects of RNA metabolism such as splicing, translation and degradation. Here, Tony Kouzarides, George Vassiliou and colleagues perform a CRISPR–Cas9 lethality screen and identify METTL3 as a gene that is essential for the growth of acute myeloid leukaemia (AML) cells. METTL3 associates with chromatin and is recruited to the promoters of active genes that are required for AML. At these gene promoters, METTL3 catalyses m6A within the coding region of the associated mRNA transcripts and enhances their translation by relieving ribosome stalling. These results indicate that METTL3 has an oncogenic role in AML and is a potential therapeutic target. 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.