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Although accumulating evidence suggests that the m<jats:sup>6<\/jats:sup>A writer METTL16 is involved in leukemia, the molecular pathway(s) by which it contributes to leukemogenesis remain unexplored. In this study, we shed light on a novel molecular mechanism whereby METTL16 plays a role in acute myeloid leukemia (AML) progression through an m<jats:sup>6<\/jats:sup>A-dependent manner. Our investigations revealed that METTL16 is overexpressed in primary AML cells. Genetic depletion of METTL16 or its pharmacological inhibition strongly affected the proliferation of AML cells, eventually triggering apoptosis. Transcriptome-wide analysis identified mRNA of MAX Dimerization Protein 4 (MXD4), a MYC pathway regulator, as a downstream target of METTL16. Mechanistically, we showed that METTL16 controls the stability of MXD4 mRNA, resulting in a reduction in MXD4 protein levels that indirectly activates the MYC-MAX axis, essential for leukemogenesis. Strikingly, the suppression of MXD4 rescued the expression levels of MYC target genes, restoring AML cell survival. 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