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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.<\/jats:p>","DOI":"10.1038\/s41389-025-00552-7","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T11:55:55Z","timestamp":1746186955000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["FLT4 activation promotes acute lymphoid leukemia survival through stabilization of MDM2\/MDMX and inactivation of p53"],"prefix":"10.1038","volume":"14","author":[{"given":"Djazia","family":"Haferssas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Dubuissez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonatan","family":"Barrera-Chimal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e9mence","family":"Messmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"El Bachir","family":"Affar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Larriv\u00e9e","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7736-0077","authenticated-orcid":false,"given":"Xue-Song","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7098-1455","authenticated-orcid":false,"given":"Casimiro","family":"Gerarduzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"552_CR1","doi-asserted-by":"crossref","unstructured":"Ferrando AA, L\u00f3pez-Ot\u00edn C. 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