期刊
HAEMATOLOGICA
卷 106, 期 12, 页码 3090-3099出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2020.274878
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类别
资金
- American University of Beirut (AUB)
- Lebanese National Council for Scientific Research (CNRSL) (Group Research Proposal GRP AUB-CNRSL)
- INSERM, CNRS, College de France, Universite de Paris
- Ligue Contre le Cancer
- TRANSCAN
- CAMELIA
- Sjoberg Foundation
- Foundation St. Joseph
The study indicates that PML is essential for RA-induced NPM-1c degradation, P53 activation, and cell death, with RA enhancing PML basal expression by inhibiting Pin1. This PML induction helps promote P53 activation, leading to a response to chemotherapy or arsenic in acute myeloid leukemia.
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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