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

Jiarui Zheng1,2, Linlin Jin1,2, Yunlong Chen1,2

  • 1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.

Leukemia
|August 21, 2025
PubMed

Insights

FLT3-ITD mutations in acute myeloid leukemia (AML) suppress the tumor suppressor p16INK4a, leading to senescence evasion and worse patient outcomes. Targeting this pathway offers a new therapeutic strategy for FLT3-ITD AML.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Cellular senescence is a key tumor-suppressive mechanism.
  • The role of senescence in FLT3-ITD-positive acute myeloid leukemia (AML) is not well understood.
  • FLT3-ITD mutations are common in AML and associated with poor prognosis.

Purpose of the Study:

  • To investigate the role of p16INK4a in FLT3-ITD-positive AML.
  • To elucidate the molecular mechanisms by which FLT3-ITD affects p16INK4a expression.
  • To identify potential therapeutic targets for FLT3-ITD AML.

Main Methods:

  • Analysis of multiple sequencing datasets from FLT3-ITD AML patients.
  • p16INK4a knockout mouse models of FLT3-ITD AML.
  • Investigation of the STAT5A-E2F3-EZH2 signaling axis.

Main Results:

  • Low p16INK4a expression in FLT3-ITD AML patients correlates with significantly worse prognoses.
  • p16INK4a knockout accelerates FLT3-ITD AML onset in mice.
  • FLT3-ITD suppresses p16INK4a via the STAT5A-E2F3-EZH2 pathway, promoting senescence evasion and malignancy.
  • A positive feedback loop exacerbates disease progression.

Conclusions:

  • The FLT3-ITD-STAT5A/E2F3/EZH2-p16INK4a axis explains poor survival in a subset of FLT3-ITD AML patients.
  • This axis represents a promising therapeutic target for refractory FLT3-ITD AML with low p16INK4a expression.

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