The study identifies METTL3 as a critical gene for the growth and maintenance of acute myeloid leukemia (AML) cells. Through CRISPR screens, METTL3 is found to be essential for AML cell survival, with its downregulation leading to cell cycle arrest, differentiation, and impaired engraftment in immunodeficient mice. METTL3 associates with chromatin and localizes to the transcriptional start sites (TSSs) of active genes, particularly those containing the CCAAT-box binding protein CEBPζ. This association results in m6A modification within the coding regions of associated mRNA transcripts, enhancing their translation by relieving ribosome stalling. The study also reveals that METTL3-regulated genes are necessary for AML, making it a potential therapeutic target for AML.The study identifies METTL3 as a critical gene for the growth and maintenance of acute myeloid leukemia (AML) cells. Through CRISPR screens, METTL3 is found to be essential for AML cell survival, with its downregulation leading to cell cycle arrest, differentiation, and impaired engraftment in immunodeficient mice. METTL3 associates with chromatin and localizes to the transcriptional start sites (TSSs) of active genes, particularly those containing the CCAAT-box binding protein CEBPζ. This association results in m6A modification within the coding regions of associated mRNA transcripts, enhancing their translation by relieving ribosome stalling. The study also reveals that METTL3-regulated genes are necessary for AML, making it a potential therapeutic target for AML.