近日，中山大学黄慧琳等研究人员合作发现，NAT10介导的mRNA N⁴-乙酰胞苷修饰重新编程丝氨酸代谢来驱动急性髓性白血病的白血病发生和干性。2024年11月6日，《自然—细胞生物学》杂志在线发表了这项成果。

研究人员表示，RNA修饰作为一种重要的表观遗传机制，已被证明在急性髓性白血病（AML）中调控异常的代谢和生长。然而，RNA N⁴-乙酰胞苷（ac4C）修饰在AML中的作用仍然不明确。

研究人员报告了ac4C及其催化酶NAT10通过重新编程丝氨酸代谢来推动白血病发生，并维持白血病干细胞/白血病起始细胞的自我更新。再机制上，NAT10通过ac4C介导的翻译增强作用，促进外源性丝氨酸的摄取和丝氨酸的从头合成。

具体而言，通过增强丝氨酸转运蛋白SLC1A4的翻译以及转录调控因子HOXA9和MENIN的作用，这些因子激活丝氨酸合成途径基因的转录。研究人员进一步将氟达拉滨鉴定为NAT10的抑制剂，并展示了NAT10的药理学抑制作用通过靶向丝氨酸代谢脆弱性，触发了显著的抗白血病效果，既在体外也在体内均得到了验证。

总的来说，该研究展示了ac4C和NAT10在代谢控制和白血病发生中的功能重要性，为针对NAT10的AML治疗提供了新思路。

附：英文原文

Title: NAT10-mediated mRNA N4-acetylcytidine reprograms serine metabolism to drive leukaemogenesis and stemness in acute myeloid leukaemia

Author: Zhang, Subo, Huang, Feng, Wang, Yushuai, Long, Yifei, Li, Yuanpei, Kang, Yalin, Gao, Weiwei, Zhang, Xiuxin, Wen, Yueting, Wang, Yun, Pan, Lili, Xia, Youmei, Yang, Zhoutian, Yang, Ying, Mo, Hongjie, Li, Baiqing, Hu, Jiacheng, Song, Yunda, Zhang, Shilin, Dong, Shenghua, Du, Xiao, Li, Yingmin, Liu, Yadi, Liao, Wenting, Gao, Yijun, Zhang, Yaojun, Chen, Hongming, Liang, Yang, Chen, Jianjun, Weng, Hengyou, Huang, Huilin

Issue&Volume: 2024-11-06

Abstract: RNA modification has emerged as an important epigenetic mechanism that controls abnormal metabolism and growth in acute myeloid leukaemia (AML). However, the roles of RNA N4-acetylcytidine (ac4C) modification in AML remain elusive. Here, we report that ac4C and its catalytic enzyme NAT10 drive leukaemogenesis and sustain self-renewal of leukaemic stem cells/leukaemia-initiating cells through reprogramming serine metabolism. Mechanistically, NAT10 facilitates exogenous serine uptake and de novo biosynthesis through ac4C-mediated translation enhancement of the serine transporter SLC1A4 and the transcription regulators HOXA9 and MENIN that activate transcription of serine synthesis pathway genes. We further characterize fludarabine as an inhibitor of NAT10 and demonstrate that pharmacological inhibition of NAT10 targets serine metabolic vulnerability, triggering substantial anti-leukaemia effects both in vitro and in vivo. Collectively, our study demonstrates the functional importance of ac4C and NAT10 in metabolism control and leukaemogenesis, providing insights into the potential of targeting NAT10 for AML therapy.

DOI: 10.1038/s41556-024-01548-y

Source: https://www.nature.com/articles/s41556-024-01548-y