Homoharringtonine Promotes FTO Degradation to Suppress LILRB4-Mediated Immune Evasion in Acute Monocytic Leukaemia.

IF 5.9 1区 生物学 Q2 CELL BIOLOGY
Fangfang Huang, Xiang Luo, Mengyu Zhang, Le Jin, Wenxin Sun, Peihan Chen, Xiuli Hong, Chenyu Xu, Meizhi Jiang, Die Hu, Bin Zhang, Shengwei Hu, Chuanjiang Yang, Rui Gao, Jinzhang Zeng, Quanyi Lu, Qiang Luo, Jun Wu, Siming Chen
{"title":"Homoharringtonine Promotes FTO Degradation to Suppress LILRB4-Mediated Immune Evasion in Acute Monocytic Leukaemia.","authors":"Fangfang Huang, Xiang Luo, Mengyu Zhang, Le Jin, Wenxin Sun, Peihan Chen, Xiuli Hong, Chenyu Xu, Meizhi Jiang, Die Hu, Bin Zhang, Shengwei Hu, Chuanjiang Yang, Rui Gao, Jinzhang Zeng, Quanyi Lu, Qiang Luo, Jun Wu, Siming Chen","doi":"10.1111/cpr.70090","DOIUrl":null,"url":null,"abstract":"<p><p>Acute monocytic leukaemia, a subtype of acute myeloid leukaemia (AML), is a highly aggressive malignancy characterised by a poor prognosis, primarily due to the ability of leukaemic cells to evade immune surveillance. In this study, we demonstrate that homoharringtonine (HHT), an FDA-approved therapeutic agent for chronic myeloid leukaemia (CML), inhibits this immune evasion by targeting the FTO/m6A/LILRB4 signalling pathway in monocytic AML. Utilising RNA sequencing (RNA-seq) and various functional assays, we reveal that HHT treatment significantly reduces LILRB4 expression at both the RNA and protein levels, suggesting that the effects of HHT on LILRB4 are distinct from its well-established role as a protein synthesis inhibitor. Mechanistically, HHT treatment markedly increases global levels of RNA m6A in THP-1 cells by promoting the degradation of FTO, which subsequently diminishes the expression of its downstream targets, MLL1 and LILRB4. Furthermore, in vitro and in vivo analyses employing monocytic AML cell lines, mouse-derived AML xenograft models, and patient samples collectively support the conclusion that HHT suppresses immune evasion in monocytic AML by reducing LILRB4 expression. Importantly, the downregulation of LILRB4 resulting from HHT treatment enhances the susceptibility of THP-1 cells to CD8<sup>+</sup> T cell cytotoxicity, accompanied by increased markers of immune activation. Overall, our findings position HHT as a promising clinical agent for enhancing CD8<sup>+</sup> T cell-based cancer immunotherapy by mitigating immune evasion in monocytic AML.</p>","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e70090"},"PeriodicalIF":5.9000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Proliferation","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1111/cpr.70090","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Acute monocytic leukaemia, a subtype of acute myeloid leukaemia (AML), is a highly aggressive malignancy characterised by a poor prognosis, primarily due to the ability of leukaemic cells to evade immune surveillance. In this study, we demonstrate that homoharringtonine (HHT), an FDA-approved therapeutic agent for chronic myeloid leukaemia (CML), inhibits this immune evasion by targeting the FTO/m6A/LILRB4 signalling pathway in monocytic AML. Utilising RNA sequencing (RNA-seq) and various functional assays, we reveal that HHT treatment significantly reduces LILRB4 expression at both the RNA and protein levels, suggesting that the effects of HHT on LILRB4 are distinct from its well-established role as a protein synthesis inhibitor. Mechanistically, HHT treatment markedly increases global levels of RNA m6A in THP-1 cells by promoting the degradation of FTO, which subsequently diminishes the expression of its downstream targets, MLL1 and LILRB4. Furthermore, in vitro and in vivo analyses employing monocytic AML cell lines, mouse-derived AML xenograft models, and patient samples collectively support the conclusion that HHT suppresses immune evasion in monocytic AML by reducing LILRB4 expression. Importantly, the downregulation of LILRB4 resulting from HHT treatment enhances the susceptibility of THP-1 cells to CD8+ T cell cytotoxicity, accompanied by increased markers of immune activation. Overall, our findings position HHT as a promising clinical agent for enhancing CD8+ T cell-based cancer immunotherapy by mitigating immune evasion in monocytic AML.

在急性单核细胞白血病中,同品杉碱促进FTO降解抑制lilrb4介导的免疫逃避。
急性单核细胞白血病是急性髓性白血病(AML)的一种亚型,是一种高度侵袭性的恶性肿瘤,其特点是预后差,主要是由于白血病细胞能够逃避免疫监测。在这项研究中,我们证明了经fda批准的治疗慢性髓性白血病(CML)的药物同质杉碱(HHT)通过靶向单核细胞AML中的FTO/m6A/LILRB4信号通路抑制这种免疫逃避。利用RNA测序(RNA-seq)和各种功能分析,我们发现HHT治疗在RNA和蛋白质水平上显著降低了LILRB4的表达,这表明HHT对LILRB4的影响不同于它作为蛋白质合成抑制剂的作用。从机制上讲,HHT处理通过促进FTO降解显著增加THP-1细胞中RNA m6A的整体水平,FTO降解随后降低其下游靶标MLL1和LILRB4的表达。此外,利用单核细胞AML细胞系、小鼠来源的AML异种移植模型和患者样本进行的体外和体内分析共同支持HHT通过降低LILRB4表达抑制单核细胞AML免疫逃避的结论。重要的是,HHT治疗导致的LILRB4下调增强了THP-1细胞对CD8+ T细胞毒性的易感性,同时伴随着免疫激活标记物的增加。总的来说,我们的研究结果表明HHT是一种有前景的临床药物,可以通过减轻单核细胞AML的免疫逃避来增强基于CD8+ T细胞的癌症免疫治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Cell Proliferation
Cell Proliferation 生物-细胞生物学
CiteScore
14.80
自引率
2.40%
发文量
198
审稿时长
1 months
期刊介绍: Cell Proliferation Focus: Devoted to studies into all aspects of cell proliferation and differentiation. Covers normal and abnormal states. Explores control systems and mechanisms at various levels: inter- and intracellular, molecular, and genetic. Investigates modification by and interactions with chemical and physical agents. Includes mathematical modeling and the development of new techniques. Publication Content: Original research papers Invited review articles Book reviews Letters commenting on previously published papers and/or topics of general interest By organizing the information in this manner, readers can quickly grasp the scope, focus, and publication content of Cell Proliferation.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信