title: Clearance of PML/RARA-bound promoters suffice to initiate APL differentiation.
abstract: PML/RARA, a potent transcriptional inhibitor of nuclear receptor signaling, represses myeloid differentiation genes and drives acute promyelocytic leukemia (APL). Association of the retinoid X receptor-α (RXRA) coreceptor to PML/RARA is required for transformation, with RXRA promoting its efficient DNA binding. APL is exquisitely sensitive to retinoic acid (RA) and arsenic trioxide (arsenic), which both trigger cell differentiation in vivo. Whereas RA elicits transcriptional activation of PML/RARA targets, how arsenic triggers differentiation remains unclear. Here we demonstrate that extinction of PML/RARA triggers terminal differentiation in vivo. Similarly, ablation of retinoid X receptors loosens PML/RARA DNA binding, inducing terminal differentiation of APL cells ex vivo or in vivo. RXRA sumoylation directly contributes to PML/RARA-dependent transformation ex vivo, presumably by enhancing transcriptional repression. Thus, APL differentiation is a default program triggered by clearance of PML/RARA-bound promoters, rather than obligatory active transcriptional activation, explaining how arsenic elicits APL maturation through PML/RARA degradation.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Paris, France; INSERM Unité Mixte de Recherche 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7212, Hôpital St. Louis, Paris, France;
authors.forename: Adeline
authors.initials: A
authors.lastname: Vitaliano-Prunier
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Paris, France; INSERM Unité Mixte de Recherche 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7212, Hôpital St. Louis, Paris, France;
authors.forename: Juliane
authors.initials: J
authors.lastname: Halftermeyer
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Paris, France; INSERM Unité Mixte de Recherche 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7212, Hôpital St. Louis, Paris, France;
authors.forename: Julien
authors.initials: J
authors.lastname: Ablain
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: Université Paris Diderot, Sorbonne Paris Cité, Paris, France; INSERM Unité Mixte de Recherche 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7212, Hôpital St. Louis, Paris, France;
authors.forename: Laurent
authors.initials: L
authors.lastname: Peres
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Paris, France; INSERM Unité Mixte de Recherche 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7212, Hôpital St. Louis, Paris, France;
authors.forename: Morgane
authors.initials: M
authors.lastname: Le Bras
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7104, INSERM U 964, Université de Strasbourg, Illkirch, France;
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Paris, France; INSERM Unité Mixte de Recherche 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7212, Hôpital St. Louis, Paris, France; Assistance Publique-Hôpitaux de Paris, Service de Biochimie, Hôpital St. Louis, Paris, France; and Collège de France, Paris, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: de Thé
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D019556:COS Cells; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D020869:Gene Expression Profiling; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D034622:RNA Interference; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058207:Sumoylation; D015533:Transcriptional Activation / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D015514:Oncogene Proteins, Fusion; D010087:Oxides; D047490:Retinoid X Receptor alpha; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D000077237:Arsenic Trioxide