A Pin1/PML/P53 axis activated by retinoic acid in NPM-1c acute myeloid leukemia

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Hleihel, Rita | El Hajj, Hiba | Wu, Hsin-Chieh | Berthier, Caroline | Zhu, Hong-Hu | Massoud, Radwan | Chakhachiro, Zaher | El Sabban, Marwan | de The, Hugues | Bazarbachi, Ali

Edité par CCSD ; Ferrata Storti Foundation -

International audience. 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.

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