Targeting p16INK4a-mediated cellular senescence as a therapeutic strategy for FLT3-ITD-driven acute myeloid leukemia

IF 13.4 1区 医学 Q1 HEMATOLOGY
Jiarui Zheng, Linlin Jin, Yunlong Chen, Yongjuan Duan, Suyu Zong, Peng Wu, Xiaofan Zhu, Wenyu Yang, Tianyuan Hu, Yingchi Zhang
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Abstract

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.

Abstract Image

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
细胞衰老是多种癌症类型的关键肿瘤抑制机制,但其在flt3 - itd阳性急性髓性白血病(AML)中的作用仍知之甚少。通过对多个测序数据集的分析,我们发现p16INK4a低表达的flt3 - itd阳性患者预后明显较差。与这些临床发现一致,小鼠p16INK4a基因敲除可加速FLT3-ITD AML发病。机制研究进一步揭示了FLT3-ITD突变通过STAT5A-E2F3-EZH2信号轴抑制p16INK4a的表达。p16INK4a的下调允许细胞逃避衰老,从而促进恶性肿瘤的增加,并建立一个加速疾病进展的正反馈循环。这一机制为该患者亚群观察到的较差的长期生存率提供了分子解释。此外,本研究中发现的FLT3-ITD- stat5a /E2F3/EZH2-p16INK4a轴是解决p16INK4a低表达难治性FLT3-ITD AML的一个有希望的治疗靶点。
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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
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
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