{"title":"Nudt15-mediated inflammatory signaling contributes to divergent outcomes in leukemogenesis and hematopoiesis","authors":"Jiachen Wang, Yu Zhang, Lei Li, Liujiao Wang, Shuainan Sun, Bowu Wang, Yanwen Ge, Zhonghui Zhang","doi":"10.1038/s41375-024-02352-1","DOIUrl":null,"url":null,"abstract":"NUDT15 encodes nucleotide triphosphate diphosphatase that is responsible for metabolizing purine analog drugs, and its genetic mutation results in severe side effects from thiopurine therapy. However, the functions of Nudt15 in leukemic stem cells (LSCs) and hematopoietic stem cells (HSCs) remain unknown. Here we reveal the Nudt15-regulating self-renewal of both mouse LSCs and HSCs. Our data show that Nudt15 negatively regulates murine leukemogenesis and its deficiency prolongs the survival of murine AML recipients by impairing LSC self-renewal, while Nudt15 ablation markedly enhances mouse HSC regenerative potential and self-renewal. Mechanistically, Nudt15 modulates inflammatory signaling in mouse LSCs and HSCs, leading to divergent self-renewal outcomes. Nudt15 depletion inhibits mouse LSC self-renewal by downregulating Ifi30, resulting in elevating intracellular ROS level. Gata2, a key regulator, is required for Nudt15-mediating inflammatory signaling in mouse HSCs. Collectively, our results present new crucial roles of Nudt15 in maintaining the functions of mouse LSC and HSC through inflammatory signaling and have a new insight into clinical implications.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8000,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Leukemia","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s41375-024-02352-1","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
NUDT15 encodes nucleotide triphosphate diphosphatase that is responsible for metabolizing purine analog drugs, and its genetic mutation results in severe side effects from thiopurine therapy. However, the functions of Nudt15 in leukemic stem cells (LSCs) and hematopoietic stem cells (HSCs) remain unknown. Here we reveal the Nudt15-regulating self-renewal of both mouse LSCs and HSCs. Our data show that Nudt15 negatively regulates murine leukemogenesis and its deficiency prolongs the survival of murine AML recipients by impairing LSC self-renewal, while Nudt15 ablation markedly enhances mouse HSC regenerative potential and self-renewal. Mechanistically, Nudt15 modulates inflammatory signaling in mouse LSCs and HSCs, leading to divergent self-renewal outcomes. Nudt15 depletion inhibits mouse LSC self-renewal by downregulating Ifi30, resulting in elevating intracellular ROS level. Gata2, a key regulator, is required for Nudt15-mediating inflammatory signaling in mouse HSCs. Collectively, our results present new crucial roles of Nudt15 in maintaining the functions of mouse LSC and HSC through inflammatory signaling and have a new insight into clinical implications.
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