A novel pathway involving METTL3, an RNA methyltransferase, is identified as essential for maintaining myeloid leukaemia. METTL3, which forms a complex with METTL14, catalyzes m6A RNA modification, a key post-transcriptional modification that regulates mRNA stability and translation. The study shows that METTL3 is essential for the growth of acute myeloid leukaemia (AML) cells, as its depletion leads to cell cycle arrest, differentiation of leukaemic cells, and failure to establish leukaemia in immunodeficient mice. METTL3 binds to chromatin and localizes to transcriptional start sites (TSS) of active genes, where it induces m6A modification in the coding region of associated mRNAs, enhancing their translation by relieving ribosome stalling. This m6A-dependent translation control is crucial for AML progression. The study used two independent CRISPR screens to identify RNA modifying enzymes necessary for AML cell survival and proliferation. METTL3 and METTL14 were identified as key players, with METTL3 showing strong negative selection in AML cells. METTL3's catalytic activity is essential for AML cell growth, and its disruption suppresses primary murine AML cell colony formation. In contrast, targeting METTL3 in non-transformed cells had no significant effect. METTL3's role in AML is further supported by its ability to promote the differentiation of leukaemic cells and reduce their engraftment in immunocompromised mice. The study also reveals that METTL3 is recruited to specific gene promoters by the transcription factor CEBPZ, which binds to the CCAAT-box. This interaction is critical for METTL3's function in m6A modification and translation control. The m6A modification of mRNAs derived from METTL3-bound genes is enriched in the coding region, contrasting with the general transcriptome where m6A is enriched in 3'UTRs. This suggests that METTL3's m6A modification is specifically involved in enhancing translation of its target mRNAs. The findings highlight METTL3 as a novel therapeutic target for AML, as its inhibition leads to differentiation of leukaemic cells and reduced proliferation. The study also identifies a new pathway for METTL3, where it is stably recruited by CEBPZ to promoters of active genes, resulting in m6A methylation of the respective mRNAs and increased translation. This pathway is critical for AML, as three of its components—METTL3, CEBPZ, and SP1—are required for AML cell growth. Together, these findings define METTL3 as a key regulator of a novel chromatin-based pathway necessary for the maintenance of the leukaemic state.A novel pathway involving METTL3, an RNA methyltransferase, is identified as essential for maintaining myeloid leukaemia. METTL3, which forms a complex with METTL14, catalyzes m6A RNA modification, a key post-transcriptional modification that regulates mRNA stability and translation. The study shows that METTL3 is essential for the growth of acute myeloid leukaemia (AML) cells, as its depletion leads to cell cycle arrest, differentiation of leukaemic cells, and failure to establish leukaemia in immunodeficient mice. METTL3 binds to chromatin and localizes to transcriptional start sites (TSS) of active genes, where it induces m6A modification in the coding region of associated mRNAs, enhancing their translation by relieving ribosome stalling. This m6A-dependent translation control is crucial for AML progression. The study used two independent CRISPR screens to identify RNA modifying enzymes necessary for AML cell survival and proliferation. METTL3 and METTL14 were identified as key players, with METTL3 showing strong negative selection in AML cells. METTL3's catalytic activity is essential for AML cell growth, and its disruption suppresses primary murine AML cell colony formation. In contrast, targeting METTL3 in non-transformed cells had no significant effect. METTL3's role in AML is further supported by its ability to promote the differentiation of leukaemic cells and reduce their engraftment in immunocompromised mice. The study also reveals that METTL3 is recruited to specific gene promoters by the transcription factor CEBPZ, which binds to the CCAAT-box. This interaction is critical for METTL3's function in m6A modification and translation control. The m6A modification of mRNAs derived from METTL3-bound genes is enriched in the coding region, contrasting with the general transcriptome where m6A is enriched in 3'UTRs. This suggests that METTL3's m6A modification is specifically involved in enhancing translation of its target mRNAs. The findings highlight METTL3 as a novel therapeutic target for AML, as its inhibition leads to differentiation of leukaemic cells and reduced proliferation. The study also identifies a new pathway for METTL3, where it is stably recruited by CEBPZ to promoters of active genes, resulting in m6A methylation of the respective mRNAs and increased translation. This pathway is critical for AML, as three of its components—METTL3, CEBPZ, and SP1—are required for AML cell growth. Together, these findings define METTL3 as a key regulator of a novel chromatin-based pathway necessary for the maintenance of the leukaemic state.