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<p>Aberrant Receptor Tyrosine Kinase (RTK) signaling allows cancer cells to modulate survival, proliferation, and death, leading to tumorigenesis and chemoresistance. In leukemia, the RTK FMS-Related Tyrosine Kinase 4 (FLT4) (also known as VEGFR3, Vascular Endothelial Growth Factor Receptor- 3) is deregulated and correlates with cancer progression. However, the underlying consequences of its deregulation remain to be determined. Moreover, chemotherapy treatment requires that cancer cells retain a wild-type p53 to respond to DNA damage by tumor-suppressing activities, i.e. apoptosis. p53 activity is predominantly limited by its two major negative regulators, MDM2 and MDMX, which inactivate p53 by promoting its degradation and/or cytoplasmic localization. In this study, we have shown that activation of FLT4 by either overexpression or binding of its ligand, VEGFC, increases MDM2/MDMX stability, inactivates p53, and leads to resistance to DNA-damaging therapies. Moreover, we found that MDMX Ser-314 phosphorylation, a consensus sequence of CDK4/6, increases MDMX stability, which subsequently affects MDM2 and p53 degradation and could be reversed by the CDK4/6 inhibitor Palbociclib. More importantly, leukemic cells treated with Palbociclib were more susceptible to DNA-damaging induction of apoptosis and had reduced cell proliferation. Leukemic cells overexpressing FLT4 displayed accelerated proliferation when injected into NOD-SCID mice as compared to wild-type cells. Altogether, our research proposes an innovative way to reactivate p53 in leukemia through the pharmacological inhibition of FLT4 signaling, which could serve as a potential treatment option.</p><p></p>

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FLT4 activation promotes acute lymphoid leukemia survival through stabilization of MDM2/MDMX and inactivation of p53

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月2日

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  • Djazia Haferssas,
  • Marion Dubuissez,
  • Jonatan Barrera-Chimal,
  • Clémence Messmer,
  • El Bachir Affar,
  • Bruno Larrivée,
  • Xue-Song Liu,
  • Casimiro Gerarduzzi

摘要

Aberrant Receptor Tyrosine Kinase (RTK) signaling allows cancer cells to modulate survival, proliferation, and death, leading to tumorigenesis and chemoresistance. In leukemia, the RTK FMS-Related Tyrosine Kinase 4 (FLT4) (also known as VEGFR3, Vascular Endothelial Growth Factor Receptor- 3) is deregulated and correlates with cancer progression. However, the underlying consequences of its deregulation remain to be determined. Moreover, chemotherapy treatment requires that cancer cells retain a wild-type p53 to respond to DNA damage by tumor-suppressing activities, i.e. apoptosis. p53 activity is predominantly limited by its two major negative regulators, MDM2 and MDMX, which inactivate p53 by promoting its degradation and/or cytoplasmic localization. In this study, we have shown that activation of FLT4 by either overexpression or binding of its ligand, VEGFC, increases MDM2/MDMX stability, inactivates p53, and leads to resistance to DNA-damaging therapies. Moreover, we found that MDMX Ser-314 phosphorylation, a consensus sequence of CDK4/6, increases MDMX stability, which subsequently affects MDM2 and p53 degradation and could be reversed by the CDK4/6 inhibitor Palbociclib. More importantly, leukemic cells treated with Palbociclib were more susceptible to DNA-damaging induction of apoptosis and had reduced cell proliferation. Leukemic cells overexpressing FLT4 displayed accelerated proliferation when injected into NOD-SCID mice as compared to wild-type cells. Altogether, our research proposes an innovative way to reactivate p53 in leukemia through the pharmacological inhibition of FLT4 signaling, which could serve as a potential treatment option.