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<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><p></p>

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

  • 期刊论文

  • 发表日期：

    2025年8月21日

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  • Jiarui Zheng,
  • Linlin Jin,
  • Yunlong Chen,
  • Yongjuan Duan,
  • Suyu Zong,
  • Peng Wu,
  • Xiaofan Zhu,
  • Wenyu Yang,
  • Tianyuan Hu,
  • Yingchi Zhang

摘要

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.