A Pin1/PML/P53 axis activated by retinoic acid in <i>NPM-1c</i> acute myeloid leukemia
Rita Hleihel, Hiba El Hajj, Hsin-Chieh Wu, Caroline Berthier, Hong‐Hu Zhu, Radwan Massoud, Zaher Chakhachiro, Marwan El Sabban, Hugues de Thé, Ali Bazarbachi
Abstract
Retinoic acid (RA) was proposed to increase survival of chemotherapy- treated patients with nucleophosmin-1 (NPM-1c)-mutated acute myeloid leukemia. 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 blast response to chemotherapy or arsenic in vivo. This RA/PML/P53 cascade could mechanistically explain RA-facilitated chemotherapy response in patients with NPM-1c mutated acute myeloid leukemia.