m6A hypermethylation of TCF-1 regulated by METTL16 promotes acute myeloid leukemia.

IF 3.2 4区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Experimental Medicine Pub Date : 2025-04-29 DOI:10.1007/s10238-025-01669-0

Jingyi Li, Hui Kang

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引用次数: 0

Abstract

Background: Methyltransferase 16 (METTL16) functions as an oncogene in various cancer, including leukemia. However, the role of METTL16 in acute myeloid leukemia (AML) is scarcely reported. The present study aimed to investigate the potential of METTL16 in AML.

Methods: RT-qPCR was used to METTL16 expression in AML patients and healthy control. m6A levels was determined using m6A assay. Methylated RNA immunoprecipitation (MeRIP) assay applied for determining m6A hypermethylation of T cell factor 1 (TCF-1) transcripts in AML cells. Chimeric antigen receptor (CAR)-T-cell functions were analyzed using flow cytometry.

Results: METTL16 is upregulated in AML patients. High levels of METTL16 were associated with poor prognosis of AML patients. Functionally, METTL16 deficiency promoted the persistence and tumor-killing ability of CAR-T cells. Moreover, METTL16 deficiency promoted the differentiation of CAR-T cells into TCF-1 precursor exhausted T cells (T_PEX). METTL16 mediated the m6A modification of TCF-1 and inhibited its mRNA expression and stability. TCF-1 deficiency promoted the exhaustion and inhibited the self-renewal ability of T cells.

Conclusion: Collectively, METTL16 deficiency promoted the persistence of CAR-T cells and memory formation in AML. Therefore, targeting METTL16 may stimulate the anti-tumor immunity in AML.

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METTL16调控的TCF-1的m6A高甲基化促进急性髓系白血病。

背景：甲基转移酶16 （METTL16）在包括白血病在内的多种癌症中起致癌基因的作用。然而，METTL16在急性髓性白血病（AML）中的作用鲜有报道。本研究旨在探讨METTL16在AML中的潜力。方法：采用RT-qPCR检测AML患者及健康对照METTL16的表达。采用m6A法测定m6A水平。甲基化RNA免疫沉淀（MeRIP）法用于检测AML细胞中T细胞因子1 （TCF-1）转录物的m6A高甲基化。用流式细胞术分析CAR - t细胞功能。结果：METTL16在AML患者中表达上调。高水平的METTL16与AML患者预后不良相关。在功能上，METTL16缺失促进了CAR-T细胞的持久性和肿瘤杀伤能力。此外，METTL16缺失促进CAR-T细胞向TCF-1前体耗竭T细胞（TPEX）分化。METTL16介导TCF-1的m6A修饰，抑制其mRNA的表达和稳定性。TCF-1缺乏促进T细胞衰竭，抑制T细胞自我更新能力。结论：总的来说，METTL16缺失促进了AML中CAR-T细胞的持久性和记忆的形成。因此，靶向METTL16可能会刺激AML的抗肿瘤免疫。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Experimental Medicine 医学-医学：研究与实验

CiteScore

4.80

自引率

2.20%

发文量

159

审稿时长

2.5 months

期刊介绍： Clinical and Experimental Medicine (CEM) is a multidisciplinary journal that aims to be a forum of scientific excellence and information exchange in relation to the basic and clinical features of the following fields: hematology, onco-hematology, oncology, virology, immunology, and rheumatology. The journal publishes reviews and editorials, experimental and preclinical studies, translational research, prospectively designed clinical trials, and epidemiological studies. Papers containing new clinical or experimental data that are likely to contribute to changes in clinical practice or the way in which a disease is thought about will be given priority due to their immediate importance. Case reports will be accepted on an exceptional basis only, and their submission is discouraged. The major criteria for publication are clarity, scientific soundness, and advances in knowledge. In compliance with the overwhelmingly prevailing request by the international scientific community, and with respect for eco-compatibility issues, CEM is now published exclusively online.