A Pin1/PML/P53 axis activated by retinoic acid in NPM-1c 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 The; Ali Bazarbachi

doi:10.3324/haematol.2020.274878

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

Haematologica. 2021 Dec 1;106(12):3090-3099. doi: 10.3324/haematol.2020.274878.

Authors

Affiliations

¹ Department of Internal Medicine, American University of Beirut, Beirut, Lebanon; Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon.
² Department of Experimental Pathology, Microbiology and Immunology, Beirut.
³ Université de Paris, INSERM UMR 944, CNRS UMR 7212, Equipe labellisée par la Ligue Nationale contre le Cancer, IRSL, Hôpital St. Louis, Paris, College de France, PSL University, CIRB, INSERM UMR 1050, CNRS UMR 7241, Paris.
⁴ Université de Paris, INSERM UMR 944, CNRS UMR 7212, Equipe labellisée par la Ligue Nationale contre le Cancer, IRSL, Hôpital St. Louis, Paris; College de France, PSL University, CIRB, INSERM UMR 1050, CNRS UMR 7241, Paris.
⁵ Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou.
⁶ Department of Internal Medicine, American University of Beirut, Beirut.
⁷ Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut.
⁸ Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut.
⁹ Department of Internal Medicine, American University of Beirut, Beirut; Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut. bazarbac@aub.edu.lb.

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.

MeSH terms

Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / genetics
Leukemia, Promyelocytic, Acute* / drug therapy
Leukemia, Promyelocytic, Acute* / genetics
Leukemia, Promyelocytic, Acute* / metabolism
NIMA-Interacting Peptidylprolyl Isomerase / genetics
NIMA-Interacting Peptidylprolyl Isomerase / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Oncogene Proteins, Fusion / metabolism
Tretinoin / pharmacology
Tretinoin / therapeutic use
Tumor Suppressor Protein p53 / genetics

Substances

NIMA-Interacting Peptidylprolyl Isomerase
Nuclear Proteins
Oncogene Proteins, Fusion
Tumor Suppressor Protein p53
Tretinoin
PIN1 protein, human

Grants and funding

Funding: This work was supported by the American University of Beirut (AUB) and the Lebanese National Council for Scientific Research (CNRSL) (Group Research Proposal GRP AUB-CNRSL) (to HEH and AB); the Paris laboratory is supported by INSERM, CNRS, College de France, Université de Paris, Ligue Contre le Cancer, TRANSCAN, CAMELIA, The Sjoberg Foundation, and Foundation St. Joseph.