<p>Wilms’ tumor 1-associated protein (WTAP) is a key N6-methyladenosine (m⁶A) methyltransferase that is upregulated in t(8;21) acute myeloid leukemia (AML) under hypoxia inducible factor 1α-mediated transcriptional activation, promoting leukemogenesis through transcriptome-wide m⁶A modifications. However, the specific substrates and intrinsic regulatory mechanisms of WTAP are not well understood. Here, we provide evidence that PHD finger protein 19 (PHF19) overexpression is regulated by WTAP-mediated m⁶A modification and promotes cell cycle progression by altering chromatin accessibility. At the same time, high expression of PHF19 and WTAP in t(8;21) AML patients indicates a worse prognosis. Furthermore, inhibition of PHF19 expression significantly suppresses the growth of t(8;21) AML cells in both in vitro and in vivo. Mechanistically, WTAP enhances the stability of PHF19 mRNA by binding to m⁶A sites in the 3’-untranslated region, thereby upregulating PHF19 expression. Conversely, WTAP suppression reduces m⁶A modification levels on the PHF19 transcript, leading to increased instability. Knockdown of PHF19 precipitates loss of H3K27 trimethylation and enhanced chromatin accessibility, ultimately resulting in upregulated expression of genes involved in the cell cycle and DNA damage checkpoints. Therefore, WTAP/m⁶A-dependent PHF19 upregulation accelerates leukemia progression by coordinating m⁶A modification and histone methylation, establishing its status as a novel therapeutic target for t(8;21) AML.</p>