The mA methyltransferase METTL14 promotes cell proliferation via SETBP1-mediated activation of PI3K-AKT signaling pathway in myelodysplastic neoplasms.

N6-methyladenosine (mA) is the most prevalent epitranscriptomic modification in mammalian mRNA. Recent studies have revealed mA is involved in the pathogenesis of various malignant tumors including hematologic neoplasms. Nevertheless, the specific roles of mA modification and mA regulators in myelodysplastic neoplasms (MDS) remain poorly understood. Herein, we demonstrated that mA level and the expression of mA methyltransferase METTL14 were elevated in MDS patients with bone marrow blasts ≥5%. Additionally, mA level and METTL14 expression were upregulated as the disease risk increased and significantly associated with adverse clinical outcomes. Knockdown of METTL14 inhibited cell proliferation and colony formation ability of MDS cells. Moreover, in vivo experiments showed METTL14 knockdown remarkably reduced tumor burden and prolonged the survival of mice. Mechanistically, METTL14 facilitated the mA modification of SETBP1 mRNA by formation of METTL3-METTL14 complex, leading to increased stabilization of SETBP1 mRNA and subsequent activation of the PI3K-AKT signaling pathway. Overall, this study elucidated the involvement of the METTL14/mA/SETBP1/PI3K-AKT signaling axis in MDS, highlighting the therapeutic potential of targeting METTL3-METTL14 complex-mediated mA modification for MDS therapy.