N6-methyladenosine (m⁶A) is the most prevalent epitranscriptomic modification in mammalian mRNA. Recent studies have revealed m⁶A is involved in the pathogenesis of various malignant tumors including hematologic neoplasms. Nevertheless, the specific roles of m⁶A modification and m⁶A regulators in myelodysplastic neoplasms (MDS) remain poorly understood. Herein, we demonstrated that m⁶A level and the expression of m⁶A methyltransferase METTL14 were elevated in MDS patients with bone marrow blasts ≥5%. Additionally, m⁶A 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 m⁶A 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/m⁶A/SETBP1/PI3K-AKT signaling axis in MDS, highlighting the therapeutic potential of targeting METTL3-METTL14 complex-mediated m⁶A modification for MDS therapy.

N6-甲基腺苷 (m ⁶ A) 是哺乳动物 mRNA 中最常见的表观转录组修饰。近年来的研究表明m ⁶ A参与包括血液肿瘤在内的多种恶性肿瘤的发病机制。然而，m ⁶ A 修饰和 m ⁶ A 调节剂在骨髓增生异常肿瘤 (MDS) 中的具体作用仍知之甚少。在此，我们证明在骨髓原始细胞≥5%的MDS患者中m ⁶ A水平和m ⁶ A甲基转移酶METTL14的表达升高。此外，随着疾病风险的增加，m ⁶ A 水平和 METTL14 表达上调，并与不良临床结果显着相关。 METTL14的敲低抑制了MDS细胞的细胞增殖和集落形成能力。此外，体内实验表明 METTL14 敲除可显着减轻肿瘤负荷并延长小鼠的存活时间。从机制上讲，METTL14 通过形成 METTL3-METTL14 复合物促进 SETBP1 mRNA 的 m ⁶ A 修饰，从而增强 SETBP1 mRNA 的稳定性并随后激活 PI3K-AKT 信号通路。总体而言，本研究阐明了 METTL14/m ⁶ A/SETBP1/PI3K-AKT 信号轴在 MDS 中的参与，强调了靶向 METTL3-METTL14 复合物介导的 m ⁶ A 修饰对 MDS 治疗的治疗潜力。