Retinoic acid (RA) was proposed to increase survival of chemotherapy-treated Nucleophosmin-1 mutated Acute Myeloid Leukemia patients (NPM-1c AMLs). We reported that ex vivo, RA triggers NPM-1c degradation, P53 activation and growth arrest. PML organizes domains that control senescence or proteolysis. Here, we demonstrate that PML is required to initiate RA-driven NPM-1c degradation, P53 activation and cell death. Mechanistically, RA enhances PML basal expression through inhibition of activated Pin1, prior to NPM-1c degradation. Such PML induction drives P53 activation, favoring blasts response to chemotherapy or arsenic in vivo. This RA/PML/P53 cascade could mechanistically explain RA-facilitated chemotherapy response in NPM-1c AML patients.
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