Hleihel Rita, Skayneh Hala, Wu Hsin-Chieh, Hamie Maguy, Kurdi Abdallah, Dakour Jana, Machaalani Charbel, El-Sabban Marwan, de Thé Hugues, Bazarbachi Ali, El Hajj Hiba
Department of Internal Medicine and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon.
Collège de France, Oncologie Cellulaire et Moléculaire, PSL Université, INSERM UMR 1050, CNRS UMR 7241, Paris, France.
Leukemia. 2025 Aug 26. doi: 10.1038/s41375-025-02731-2.
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.
核磷蛋白-1（NPM1）是一种核仁伴侣蛋白，在急性髓系白血病（AML）中经常发生突变。ARF和Sentrin/SUMO特异性蛋白酶3（SENP3）通过动态SUMO化/去SUMO化来控制NPM1的功能。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。研究报告称，当将维甲酸（RA）添加到化疗或去甲基化药物中时，NPM1c AML患者的生存率会提高。在体外，RA会引发NPM1c降解、P53激活和细胞死亡。然而，其中涉及的分子机制仍然难以捉摸。在这里，我们表明，在NPM1c AML细胞系或患者的原始细胞中，NPM1c引发的线粒体功能障碍和氧化应激通过上调SENP3来驱动NPM1c的稳定。RA可减少线粒体ROS的产生，促使SENP3降解、ARF稳定、PML依赖的NPM1c超SUMO化，随后是RNF4依赖的泛素化和降解。因此，RA引发的线粒体适应性增强可中断稳定NPM1c蛋白的反馈回路，从机制上解释了RA在化疗或去甲基化药物治疗的AML中的益处。
