维甲酸破坏急性髓系白血病的NPM1c/ROS/SENP3/ARF致癌轴

IF 13.4 1区 医学 Q1 HEMATOLOGY
Rita Hleihel, Hala Skayneh, Hsin-Chieh Wu, Maguy Hamie, Abdallah Kurdi, Jana Dakour, Charbel Machaalani, Marwan El-Sabban, Hugues de Thé, Ali Bazarbachi, Hiba El Hajj
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引用次数: 0

摘要

核磷蛋白-1 (NPM1)是一种在急性髓性白血病(AML)中经常发生突变的核仁伴侣蛋白。ARF和Sentrin/SUMO特异性肽酶3 (SENP3)通过动态SUMOylation/去SUMOylation控制NPM1功能。突变的NPM1是一种癌蛋白,表现出异常的细胞质定位(NPM1c)并破坏PML/P53信号传导。研究报道,当视黄酸(RA)加入化疗或低甲基化药物时,NPM1c AML患者的生存率增加。在体外,RA启动NPM1c降解、P53激活和细胞死亡。然而,涉及的分子机制仍然难以捉摸。本研究表明,在NPM1c AML细胞系或患者原细胞中,NPM1c触发的线粒体功能障碍和氧化应激通过SENP3上调驱动NPM1c稳定。RA减少线粒体ROS生成,驱动SENP3降解、ARF稳定、pml依赖的NPM1c高sumoylation,随后是rnf4依赖的泛素化和降解。因此,稳定NPM1c蛋白的反馈回路可以被RA触发的线粒体适应性增强所中断,这从机制上解释了RA在化疗或低甲基化药物治疗aml中的益处。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Retinoic acid disrupts an NPM1c/ROS/SENP3/ARF oncogenic axis in acute myeloid leukemia

Retinoic acid disrupts an NPM1c/ROS/SENP3/ARF oncogenic axis in acute myeloid leukemia

Nucleophosmin-1 (NPM1) is a nucleolar chaperone protein frequently mutated in acute myeloid leukemia (AML). ARF and Sentrin/SUMO Specific Peptidase 3 (SENP3) control NPM1 functions through dynamic SUMOylation/de-SUMOylation. Mutated NPM1 is an oncoprotein that exhibits an aberrant cytoplasmic localization (NPM1c) and disrupts PML/P53 signaling. Studies reported increased survival of patients with NPM1c AML when retinoic acid (RA) was added to chemotherapy or hypomethylating agents. Ex vivo, RA initiates NPM1c degradation, P53 activation and cell death. Yet, the molecular mechanisms involved remain elusive. Here we show that in NPM1c AML cell lines or patients’ blasts, NPM1c-triggered mitochondrial dysfunction and oxidative stress drive NPM1c stabilization through SENP3 upregulation. RA decreases mitochondrial ROS production, driving degradation of SENP3, ARF stabilization, PML-dependent NPM1c hyperSUMOylation followed by RNF4-dependent ubiquitination and degradation. Thus, the feedback loop stabilizing NPM1c protein can be interrupted by RA-triggered enhanced mitochondrial fitness, mechanistically explaining the benefit of RA in chemotherapy or hypomethylating agents-treated AMLs.

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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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