title: Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells.
abstract: Nucleophosmin-1 (NPM1) is the most frequently mutated gene in acute myeloid leukemia (AML). Addition of retinoic acid (RA) to chemotherapy was proposed to improve survival of some of these patients. Here, we found that RA or arsenic trioxide synergistically induce proteasomal degradation of mutant NPM1 in AML cell lines or primary samples, leading to differentiation and apoptosis. NPM1 mutation not only delocalizes NPM1 from the nucleolus, but it also disorganizes promyelocytic leukemia (PML) nuclear bodies. Combined RA/arsenic treatment significantly reduced bone marrow blasts in 3 patients and restored the subnuclear localization of both NPM1 and PML. These findings could explain the proposed benefit of adding RA to chemotherapy in NPM1 mutant AMLs, and warrant a broader clinical evaluation of regimen comprising a RA/arsenic combination.
authors: Department of Internal Medicine, Department of Experimental Pathology, Microbiology and Immunology, and.
authors: Hiba
authors: H
authors: El Hajj
authors: Department of Internal Medicine, Department of Cell Biology, Anatomy and Physiological Sciences, American University of Beirut, Beirut, Lebanon;
authors: Zeina
authors: Z
authors: Dassouki
authors: INSERM/Centre National de la Recherche Scientifique/University Paris Diderot, Unités Mixtes de Recherche 944/7212, Collège de France and Equipe labellisée Ligue contre le Cancer.
authors: Caroline
authors: C
authors: Berthier
authors: Service d'Hématologie Clinique, and.
authors: Emmanuel
authors: E
authors: Raffoux
authors: Service d'Hématologie Senior, Hôpital St. Louis, Paris, France; Service d'Hématologie Clinique, Hôpital Avicenne, Bobigny, France;
authors: Lionel
authors: L
authors: Ades
authors: INSERM U938, and Service d'Hématologie, Hôpital St. Antoine, Paris, France; Université Pierre et Marie Curie, Paris, France;
authors: Olivier
authors: O
authors: Legrand
authors: Department of Internal Medicine, Department of Cell Biology, Anatomy and Physiological Sciences, American University of Beirut, Beirut, Lebanon;
authors: Rita
authors: R
authors: Hleihel
authors: INSERM/Centre National de la Recherche Scientifique/University Paris Diderot, Unités Mixtes de Recherche 944/7212, Collège de France and Equipe labellisée Ligue contre le Cancer.
authors: Umut
authors: U
authors: Sahin
authors: Department of Internal Medicine, Department of Experimental Pathology, Microbiology and Immunology, and.
authors: Nadim
authors: N
authors: Tawil
authors: Department of Internal Medicine, Department of Experimental Pathology, Microbiology and Immunology, and.
authors: Ala
authors: A
authors: Salameh
authors: ER045, Laboratory of Stem Cells, Department of Biology, Faculty of Sciences, Lebanese University, Beirut, Lebanon; and.
authors: Kazem
authors: K
authors: Zibara
authors: Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.
authors: Nadine
authors: N
authors: Darwiche
authors: INSERM U938, and Service d'Hématologie, Hôpital St. Antoine, Paris, France; Université Pierre et Marie Curie, Paris, France;
authors: Mohamad
authors: M
authors: Mohty
authors: Service d'Hématologie Clinique, and.
authors: Hervé
authors: H
authors: Dombret
authors: Service d'Hématologie Senior, Hôpital St. Louis, Paris, France; Service d'Hématologie Clinique, Hôpital Avicenne, Bobigny, France;
authors: Pierre
authors: P
authors: Fenaux
authors: INSERM/Centre National de la Recherche Scientifique/University Paris Diderot, Unités Mixtes de Recherche 944/7212, Collège de France and Equipe labellisée Ligue contre le Cancer.
authors: Hugues
authors: H
authors: de Thé
authors: Department of Internal Medicine, Department of Cell Biology, Anatomy and Physiological Sciences, American University of Beirut, Beirut, Lebanon;
authors: Ali
authors: A
authors: Bazarbachi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050505:Mutant Proteins / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D010087:Oxides / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D001152:Arsenicals; D050505:Mutant Proteins; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D010087:Oxides; D000090243:Nucleophosmin; D014212:Tretinoin; D000077237:Arsenic Trioxide