Department of Hematology, First Affiliated Hospital of Bengbu Medical University, Anhui Province, China.
Department of Hematology, First Affiliated Hospital of Bengbu Medical University, Anhui Province, China.
Cell Signal. 2024 Oct;122:111304. doi: 10.1016/j.cellsig.2024.111304. Epub 2024 Jul 20.
Acute myeloid leukemia (AML) is a prevalent hematologic malignancy characterized by a steady rise in morbidity and mortality rates over time. The upregulation of methyltransferase-like 14 (METTL14) expression in AML has been identified; however, its specific contributions to AML progression and underlying molecular mechanisms have yet to be elucidated.
METTL14-bound mRNAs were predicted using bioinformatics methods, analyzed, and screened to identify T-complex protein 1 (TCP1). The regulatory impact of METTL14 on TCP1 was observed. TCP1 expression in AML clinical samples was assessed using quantitative real-time PCR and western blot analysis. The involvement of TCP1 in AML malignant progression was assessed through in vitro and in vivo functional assays. The String database was utilized for predicting proteins that interact with TCP1, while western blot assays and immunoprecipitation were employed to validate the associated signaling pathways.
METTL14 overexpression upregulates TCP1 expression in AML cells. AML patients exhibit high levels of TCP1 expression. Elevated TCP1 levels in HL60 and U937 cells in vitro lead to increased proliferation, migration, invasion, and inhibition of apoptosis, while in vivo, it accelerates AML proliferation and tumorigenesis. Mechanistically, METTL14 modulates AML progression by influencing TCP1 transcript stability via m6A methylation, thereby regulating TCP1 expression. Additionally, PPP2R2C potentially serves as a crucial functional target of TCP1 implicated in the malignant progression of AML.
Upregulation of TCP1 expression in AML through METTL14-mediated m6A modification accelerates the malignant progression of the disease. Therefore, targeting the m6A modification of TCP1 could be a potential therapeutic strategy to enhance the treatment of AML.
急性髓系白血病（AML）是一种常见的血液恶性肿瘤，其发病率和死亡率随着时间的推移呈稳步上升趋势。在 AML 中，甲基转移酶样 14（METTL14）的表达上调已经被确定；然而，其对 AML 进展的具体贡献及其潜在的分子机制尚未阐明。
使用生物信息学方法预测 METTL14 结合的 mRNA，进行分析和筛选，以鉴定 T 复合物蛋白 1（TCP1）。观察 METTL14 对 TCP1 的调控影响。使用定量实时 PCR 和 Western blot 分析评估 AML 临床样本中 TCP1 的表达。通过体外和体内功能测定评估 TCP1 在 AML 恶性进展中的作用。使用 String 数据库预测与 TCP1 相互作用的蛋白质，同时使用 Western blot 测定和免疫沉淀验证相关信号通路。
METTL14 过表达上调 AML 细胞中 TCP1 的表达。AML 患者表现出高水平的 TCP1 表达。体外 HL60 和 U937 细胞中 TCP1 水平的升高导致增殖、迁移、侵袭增加和凋亡抑制，而体内则加速 AML 的增殖和肿瘤发生。机制上，METTL14 通过 m6A 甲基化影响 TCP1 转录本的稳定性来调节 AML 进展，从而调节 TCP1 的表达。此外，PPP2R2C 可能是 TCP1 的一个关键功能靶标，参与 AML 的恶性进展。
METTL14 介导的 m6A 修饰上调 AML 中 TCP1 的表达，加速疾病的恶性进展。因此，靶向 TCP1 的 m6A 修饰可能是增强 AML 治疗的潜在治疗策略。
