{"title":"靶向p16ink4a介导的细胞衰老作为flt3 - itd驱动的急性髓系白血病的治疗策略","authors":"Jiarui Zheng, Linlin Jin, Yunlong Chen, Yongjuan Duan, Suyu Zong, Peng Wu, Xiaofan Zhu, Wenyu Yang, Tianyuan Hu, Yingchi Zhang","doi":"10.1038/s41375-025-02743-y","DOIUrl":null,"url":null,"abstract":"<p>Cellular senescence serves as a critical tumor-suppressive mechanism across various cancer types, yet its role in <i>FLT3</i>-ITD-positive acute myeloid leukemia (AML) remains poorly understood. Through the analysis of multiple sequencing datasets, we identified that <i>FLT3</i>-ITD-positive patients with low <i>p16</i><sup><i>INK4a</i></sup> expression have significantly worse prognoses. Consistent with these clinical findings, knockout of <i>p16</i><sup><i>INK4a</i></sup> in mice was shown to accelerate <i>FLT3</i>-ITD AML onset. Mechanistic investigations further revealed that the <i>FLT3</i>-ITD mutation suppresses <i>p16</i><sup><i>INK4a</i></sup> expression via the STAT5A-E2F3-EZH2 signaling axis. This downregulation of <i>p16</i><sup><i>INK4a</i></sup> allows cells to evade senescence, thereby promoting increased malignancy and establishing a positive feedback loop that exacerbates disease progression. This mechanism provides a molecular explanation for the poorer long-term survival observed in this patient subset. Furthermore, the <i>FLT3</i>-ITD-STAT5A/E2F3/EZH2-<i>p16</i><sup><i>INK4a</i></sup> axis identified in this study represents a promising therapeutic target for addressing refractory <i>FLT3</i>-ITD AML with low <i>p16</i><sup><i>INK4a</i></sup> expression.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"21 1","pages":""},"PeriodicalIF":13.4000,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeting p16INK4a-mediated cellular senescence as a therapeutic strategy for FLT3-ITD-driven acute myeloid leukemia\",\"authors\":\"Jiarui Zheng, Linlin Jin, Yunlong Chen, Yongjuan Duan, Suyu Zong, Peng Wu, Xiaofan Zhu, Wenyu Yang, Tianyuan Hu, Yingchi Zhang\",\"doi\":\"10.1038/s41375-025-02743-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Cellular senescence serves as a critical tumor-suppressive mechanism across various cancer types, yet its role in <i>FLT3</i>-ITD-positive acute myeloid leukemia (AML) remains poorly understood. Through the analysis of multiple sequencing datasets, we identified that <i>FLT3</i>-ITD-positive patients with low <i>p16</i><sup><i>INK4a</i></sup> expression have significantly worse prognoses. Consistent with these clinical findings, knockout of <i>p16</i><sup><i>INK4a</i></sup> in mice was shown to accelerate <i>FLT3</i>-ITD AML onset. Mechanistic investigations further revealed that the <i>FLT3</i>-ITD mutation suppresses <i>p16</i><sup><i>INK4a</i></sup> expression via the STAT5A-E2F3-EZH2 signaling axis. This downregulation of <i>p16</i><sup><i>INK4a</i></sup> allows cells to evade senescence, thereby promoting increased malignancy and establishing a positive feedback loop that exacerbates disease progression. This mechanism provides a molecular explanation for the poorer long-term survival observed in this patient subset. Furthermore, the <i>FLT3</i>-ITD-STAT5A/E2F3/EZH2-<i>p16</i><sup><i>INK4a</i></sup> axis identified in this study represents a promising therapeutic target for addressing refractory <i>FLT3</i>-ITD AML with low <i>p16</i><sup><i>INK4a</i></sup> expression.</p><figure></figure>\",\"PeriodicalId\":18109,\"journal\":{\"name\":\"Leukemia\",\"volume\":\"21 1\",\"pages\":\"\"},\"PeriodicalIF\":13.4000,\"publicationDate\":\"2025-08-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Leukemia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41375-025-02743-y\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Leukemia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41375-025-02743-y","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
Targeting p16INK4a-mediated cellular senescence as a therapeutic strategy for FLT3-ITD-driven acute myeloid leukemia
Cellular senescence serves as a critical tumor-suppressive mechanism across various cancer types, yet its role in FLT3-ITD-positive acute myeloid leukemia (AML) remains poorly understood. Through the analysis of multiple sequencing datasets, we identified that FLT3-ITD-positive patients with low p16INK4a expression have significantly worse prognoses. Consistent with these clinical findings, knockout of p16INK4a in mice was shown to accelerate FLT3-ITD AML onset. Mechanistic investigations further revealed that the FLT3-ITD mutation suppresses p16INK4a expression via the STAT5A-E2F3-EZH2 signaling axis. This downregulation of p16INK4a allows cells to evade senescence, thereby promoting increased malignancy and establishing a positive feedback loop that exacerbates disease progression. This mechanism provides a molecular explanation for the poorer long-term survival observed in this patient subset. Furthermore, the FLT3-ITD-STAT5A/E2F3/EZH2-p16INK4a axis identified in this study represents a promising therapeutic target for addressing refractory FLT3-ITD AML with low p16INK4a expression.
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