PTPN2 Inhibition Disrupts Mitochondrial Renewal and Blocks TFRC-Mediated Mitophagy to Exert Anti-Tumor Activities in ALK-Positive Anaplastic Large Cell Lymphoma.

IF 14.1 1区 材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Wei-Ting Wang, Zi-Wen Duan, Tong-Yao Xing, Wei Hua, Kai-Xing Du, Chun-Yu Shang, Yi-Fan Wu, Li Wang, Jian-Yong Li, Rui Gao, Jin-Hua Liang, Wei Xu
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Abstract

Anaplastic large cell lymphoma (ALCL) is a heterogeneous subtype of T-cell lymphoma usually driven by genetic alterations affecting the anaplastic lymphoma kinase (ALK) gene. Despite the relatively favorable prognosis of ALK-positive (ALK+) ALCL, approximately 30-40% of patients experience relapses or disease progression. This work identifies protein tyrosine phosphatase PTPN2 as a critical gene essential for the growth and survival of ALK+ ALCL by CRISPR/Cas9 editing. PTPN2 depletion can significantly suppress tumor cell proliferation, induce apoptosis, and provoke cell cycle arrest. Mechanistically, PTPN2 negatively regulates transferrin receptor (TFRC) expression to promote mitochondrial renewal via PTEN induced kinase 1 (PINK1)-PRKN (parkin RBR E3 ubiquitin protein ligase)-mediated mitophagy. The process functions independently of ferroptosis. Interestingly, TFRC is directly regulated by the transcription factor hypoxia-inducible factor 1 alpha (HIF1A) in its promoter. Notably, an orally bioavailable potent PTPN2/N1 active-site inhibitor ABBV-CLS-484 (AC484) demonstrates significant therapeutic potential against ALK+ ALCL by disturbing mitochondrial renewal and blocking TFRC-mediated PINK1-PRKN-dependent mitophagy to exert anti-tumor activities, providing critical insights into the selection of targeted treatment strategies for ALK+ ALCL patients and a strong rationale for advancing AC484 into clinical trials.

在alk阳性间变性大细胞淋巴瘤中,PTPN2抑制破坏线粒体更新并阻断tfrc介导的线粒体自噬发挥抗肿瘤活性
间变性大细胞淋巴瘤(ALCL)是t细胞淋巴瘤的一种异质性亚型,通常由影响间变性淋巴瘤激酶(ALK)基因的遗传改变驱动。尽管ALK阳性(ALK+) ALCL的预后相对较好,但大约30-40%的患者会出现复发或疾病进展。这项工作通过CRISPR/Cas9编辑鉴定了蛋白酪氨酸磷酸酶PTPN2是ALK+ ALCL生长和存活所必需的关键基因。PTPN2缺失可显著抑制肿瘤细胞增殖,诱导细胞凋亡,引起细胞周期阻滞。机制上,PTPN2负调控转铁蛋白受体(TFRC)表达,通过PTEN诱导的激酶1 (PINK1)-PRKN (parkin RBR E3泛素蛋白连接酶)介导的线粒体自噬促进线粒体更新。该过程独立于铁下垂而起作用。有趣的是,TFRC是由其启动子中的转录因子缺氧诱导因子1 α (HIF1A)直接调控的。值得注意的是,口服有效的PTPN2/N1活性位点抑制剂ABBV-CLS-484 (AC484)通过干扰线粒体更新和阻断tfrc介导的pink1 - prk依赖的线粒体自噬来发挥抗肿瘤活性,显示出对ALK+ ALCL的显著治疗潜力,为ALK+ ALCL患者选择靶向治疗策略提供了重要的认识,并为推进AC484进入临床试验提供了强有力的理由。
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
Advanced Science
Advanced Science CHEMISTRY, MULTIDISCIPLINARYNANOSCIENCE &-NANOSCIENCE & NANOTECHNOLOGY
CiteScore
18.90
自引率
2.60%
发文量
1602
审稿时长
1.9 months
期刊介绍: Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.
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