title: The PML domain of PML-RARα blocks senescence to promote leukemia.
abstract: In most acute promyelocytic leukemia (APL) cases, translocons produce a promyelocytic leukemia protein-retinoic acid receptor α (PML-RARα) fusion gene. Although expression of the human PML fusion in mice promotes leukemia, its efficiency is rather low. Unexpectedly, we find that simply replacing the human PML fusion with its mouse counterpart results in a murine PML-RARα (mPR) hybrid protein that is transformed into a significantly more leukemogenic oncoprotein. Using this more potent isoform, we show that mPR promotes immortalization by preventing cellular senescence, impeding up-regulation of both the p21 and p19(ARF) cell-cycle regulators. This induction coincides with a loss of the cancer-associated ATRX/Daxx-histone H3.3 predisposition complex and suggests inhibition of senescence as a targetable mechanism in APL therapy.
authors.affiliation: Research Institute Children's Cancer Center Hamburg, 20251 Hamburg, Germany;
authors.forename: Katharina
authors.initials: K
authors.lastname: Korf
authors.affiliation: Microbiologie Fondamental et Pathogénicité, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5234, University of Bordeaux Segalen, 33076 Bordeaux, France;
authors.forename: Harald
authors.initials: H
authors.lastname: Wodrich
authors.affiliation: Research Institute Children's Cancer Center Hamburg, 20251 Hamburg, Germany;
authors.forename: Alexander
authors.initials: A
authors.lastname: Haschke
authors.affiliation: Gene Expression Laboratory.
authors.forename: Corinne
authors.initials: C
authors.lastname: Ocampo
authors.affiliation: Research Institute Children's Cancer Center Hamburg, 20251 Hamburg, Germany;
authors.forename: Lena
authors.initials: L
authors.lastname: Harder
authors.affiliation: Research Institute Children's Cancer Center Hamburg, 20251 Hamburg, Germany;
authors.forename: Friederike
authors.initials: F
authors.lastname: Gieseke
authors.affiliation: Research Institute Children's Cancer Center Hamburg, 20251 Hamburg, Germany;
authors.forename: Annika
authors.initials: A
authors.lastname: Pollmann
authors.affiliation: Research Institute Children's Cancer Center Hamburg, 20251 Hamburg, Germany;
authors.forename: Kevin
authors.initials: K
authors.lastname: Dierck
authors.affiliation: Research Institute Children's Cancer Center Hamburg, 20251 Hamburg, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Prall
authors.affiliation: Department of General Virology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany; and.
authors.forename: Hannah
authors.initials: H
authors.lastname: Staege
authors.affiliation: Molecular and Cell Biology Laboratory, and.
authors.forename: Hui
authors.initials: H
authors.lastname: Ma
authors.affiliation: Research Institute Children's Cancer Center Hamburg, 20251 Hamburg, Germany;Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg, 20246 Hamburg, Germany.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Horstmann
authors.affiliation: Gene Expression Laboratory,Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037; evans@salk.edu sternsdorf@kinderkrebs-forschung.de.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.affiliation: Research Institute Children's Cancer Center Hamburg, 20251 Hamburg, Germany; evans@salk.edu sternsdorf@kinderkrebs-forschung.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sternsdorf
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000503:physiopathology*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin
keywords: PML nuclear bodies; hematopoiesis; histone chaperones; leukemogenesis; oncogenes
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