USP5 inhibition enables potential therapy for t(8;21) AML through ubiquitin-mediated AML1-ETO degradation in patient-derived xenografts

IF 14.6 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2025-09-24 DOI:10.1126/scitranslmed.adt9100

Lan Ma, Kun Zhang, Zixuan Zhang, Chenyang Wang, Mengyuan Ma, Ying Liu, Yanli Zhao, Ziqing Gong, Ning Liu, Mingming Wei, Xiang Liu, Jingfeng Zhou, Shuangwei Liu, Cheng Yang, Guang Yang

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引用次数: 0

Abstract

The AML1-ETO (AE) fusion protein is a key target for treating t(8;21) acute myeloid leukemia (AML). In this investigation, we identified ubiquitin-specific protease 5 (USP5) as the deubiquitinating enzyme of AE. USP5 knockdown decreased AML cell growth and induced differentiation both in vitro and in vivo. In addition, we developed a high-throughput screening (HTS) method and identified a potent, selective USP5 inhibitor, WCY-8-67. This lead compound was identified as a selective USP5 inhibitor by targeting the ubiquitin-associated domain 2 (UBA2) region. It also induced aggregation and precipitation of the target protein, which led to USP5 dysfunction. WCY-8-67 exhibited excellent in vivo bioavailability and tolerability, and it effectively inhibited the growth of AML cells in animal models. In addition, in a patient-derived xenograft (PDX) model, this compound, when combined with 5-azacytidine (5-Aza), improved therapeutic effects. This study presents promising targeted therapeutic possibilities for the treatment of t(8;21) AML that require further study.

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USP5抑制使患者来源的异种移植物中泛素介导的AML1-ETO降解成为治疗t(8;21) AML的潜在疗法

AML1-ETO （AE）融合蛋白是治疗t（8;21）急性髓性白血病（AML）的关键靶点。在这项研究中，我们确定了泛素特异性蛋白酶5 （USP5）是AE的去泛素化酶。在体外和体内，USP5敲低可抑制AML细胞生长并诱导分化。此外，我们开发了一种高通量筛选（HTS）方法，并鉴定了一种有效的、选择性的USP5抑制剂WCY-8-67。该先导化合物通过靶向泛素相关结构域2 （UBA2）区域被鉴定为选择性USP5抑制剂。它还诱导了靶蛋白的聚集和沉淀，从而导致USP5功能障碍。WCY-8-67具有良好的体内生物利用度和耐受性，在动物模型中有效抑制AML细胞的生长。此外，在患者来源的异种移植物（PDX）模型中，该化合物与5-氮杂胞苷（5-Aza）联合使用时，改善了治疗效果。这项研究为治疗t(8;21) AML提供了有希望的靶向治疗可能性，但需要进一步研究。

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

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.