title: Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure.
abstract: Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)-retinoic acid receptor-α (PML-RARA) fusion protein, which interferes with nuclear receptor signaling and PML nuclear body (NB) assembly. APL is the only malignancy definitively cured by targeted therapies: retinoic acid (RA) and/or arsenic trioxide, which both trigger PML-RARA degradation through nonoverlapping pathways. Yet, the cellular and molecular determinants of treatment efficacy remain disputed. We demonstrate that a functional Pml-transformation-related protein 53 (Trp53) axis is required to eradicate leukemia-initiating cells in a mouse model of APL. Upon RA-induced PML-RARA degradation, normal Pml elicits NB reformation and induces a Trp53 response exhibiting features of senescence but not apoptosis, ultimately abrogating APL-initiating activity. Apart from triggering PML-RARA degradation, arsenic trioxide also targets normal PML to enhance NB reformation, which may explain its clinical potency, alone or with RA. This Pml-Trp53 checkpoint initiated by therapy-triggered NB restoration is specific for PML-RARA-driven APL, but not the RA-resistant promyelocytic leukemia zinc finger (PLZF)-RARA variant. Yet, as NB biogenesis is druggable, it could be therapeutically exploited in non-APL malignancies.
authors.affiliation: 1] Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, Paris, France. [2] INSERM UMR 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris, France. [3] CNRS UMR 7212, Hôpital St. Louis, Paris, France. [4].
authors.forename: Julien
authors.initials: J
authors.lastname: Ablain
authors.affiliation: 1] Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, Paris, France. [2] INSERM UMR 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris, France. [3] CNRS UMR 7212, Hôpital St. Louis, Paris, France.
authors.forename: Kim
authors.initials: K
authors.lastname: Rice
authors.affiliation: 1] Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, Paris, France. [2] INSERM UMR 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris, France. [3] CNRS UMR 7212, Hôpital St. Louis, Paris, France.
authors.forename: Hassane
authors.initials: H
authors.lastname: Soilihi
authors.affiliation: Programme Cartes d'Identité des Tumeurs, Ligue Nationale contre le Cancer, Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reynies
authors.affiliation: 1] Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. [2] Department of Biosciences, University of Milan, Milan, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.affiliation: 1] Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, Paris, France. [2] INSERM UMR 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris, France. [3] CNRS UMR 7212, Hôpital St. Louis, Paris, France. [4] Assistance Publique Hôpitaux de Paris, Service de Biochimie, Hôpital St. Louis, Paris, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: de Thé
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D019295:Computational Biology; D006801:Humans; D053208:Kaplan-Meier Estimate; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D046228:Microarray Analysis; D009687:Nuclear Proteins / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology; D000071156:Promyelocytic Leukemia Protein; D059748:Proteolysis / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology*; D000072482:Retinoic Acid Receptor alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D001152:Arsenicals; D009687:Nuclear Proteins; D010087:Oxides; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014212:Tretinoin; D000077237:Arsenic Trioxide