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
{"title":"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","authors":"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","doi":"10.1126/scitranslmed.adt9100","DOIUrl":null,"url":null,"abstract":"<div >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.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 817","pages":""},"PeriodicalIF":14.6000,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"USP5 inhibition enables potential therapy for t(8;21) AML through ubiquitin-mediated AML1-ETO degradation in patient-derived xenografts\",\"authors\":\"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\",\"doi\":\"10.1126/scitranslmed.adt9100\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >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.</div>\",\"PeriodicalId\":21580,\"journal\":{\"name\":\"Science Translational Medicine\",\"volume\":\"17 817\",\"pages\":\"\"},\"PeriodicalIF\":14.6000,\"publicationDate\":\"2025-09-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Translational Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/scitranslmed.adt9100\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.adt9100","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
USP5 inhibition enables potential therapy for t(8;21) AML through ubiquitin-mediated AML1-ETO degradation in patient-derived xenografts
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.
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.