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Ferrata Storti Foundation
Haematologica 2021 Volume 106(12):3090-3099
A Pin1/PML/P53 axis activated by retinoic acid in NPM-1c acute myeloid leukemia
Rita Hleihel,1,2* Hiba El Hajj,3* Hsin-Chieh Wu,4-6* Caroline Berthier,4-6 Hong-Hu Zhu,7 Radwan Massoud,1 Zaher Chakhachiro,8 Marwan El Sabban,2 Hugues de The4-6# and Ali Bazarbachi1,2#
1Department of Internal Medicine, American University of Beirut, Beirut, Lebanon; 2Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon; 3Department of Experimental Pathology, Immunology and Microbiology, Beirut, Lebanon; 4Université de Paris, INSERM UMR 944, CNRS UMR 7212, Equipe labellisée par la Ligue Nationale Contre le Cancer, IRSL, Hôpital St. Louis, Paris, France; 5Oncologie Moléculaire, Hôpital St. Louis, Paris, France; 6Collège de France, PSL University, CIRB, INSERM UMR 1050, CNRS UMR 7241, Paris, France; 7Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China and 8Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut, Lebanon
*RH, HEH and HCW contributed equally as co-first authors. #HDT and AB contributed equally as co-senior authors.
ABSTRACT
Retinoic acid (RA) was proposed to increase survival of chemother- apy-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 acti- vation and cell death. Mechanistically, RA enhances PML basal expres- sion 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 mech- anistically explain RA-facilitated chemotherapy response in patients with NPM-1c mutated acute myeloid leukemia.
Introduction
Nucleophosmin 1 (NPM-1) is a chaperone implicated in multiple processes, notably ribosomal biogenesis and growth control. NPM-1 alterations have been directly implicated in cancer development, through a variety of mechanisms, includ- ing chromosomal translocations and recurrent mutations.1 In acute myeloid leukemia (AML), the most prevalent one is a short nucleotide insertion that induces a frame shift in the C-terminus of the protein, yielding NPM-1c.2 NPM-1c has been demon- strated to have multiple properties, including inhibition of P53 and cytoplasmic sequestration of key regulatory proteins.3,4 AML with NPM-1 mutation is the most common subtype, accounting for more than one-third of AML. More than half of the patients ultimately relapse when treated with conventional chemotherapy. NPM-1- associated cases of AML in relapsed or elderly patients unfit for chemotherapy rep- resent a major unmet medical need.
Retinoic acid (RA) is a hormone with multiple effects on development and tissue homeostasis. RA has a dual effect on stem cell fate and differentiation following modulation of transcription. High doses of RA have also been shown to inhibit Pin1, a protein-modifying enzyme involved in the activation of multiple growth suppres- sive pathways.5,6 RA demonstrated unambiguous clinical efficacy in a variety of con- ditions including neuroblastoma and acute promyelocytic leukemia (APL).7 In APL, RA directly targets the driving PML/RARA oncoprotein for degradation and pro- duces complete remissions8 through activation of a PML/P53 senescence check- point.9,10 In other AML, in vitro studies suggested some efficacy of RA.11,12 However, contradictory results emerged from clinical trials investigating the efficacy of RA in non-APL AML.13 Whereas an Austrian-German study (AML HD98B) found that the addition of RA to intensive chemotherapy improved remission, event-free survival,
Acute Myeloid Leukemia
Correspondence:
ALI BAZARBACHI
bazarbac@aub.edu.lb
Received: October 24, 2020. Accepted: May 3, 2021. Pre-published: May 27, 2021.
https://doi.org/10.3324/haematol.2020.274878 ©2021 Ferrata Storti Foundation
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