Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells.

Nadim Tawil, Ali Bazarbachi, Hugues de Thé, Pierre Fenaux, Hervé Dombret, Mohamad Mohty, Nadine Darwiche, Kazem Zibara, Ala Salameh, Hiba El Hajj, Umut Sahin, Rita Hleihel, Olivier Legrand, Lionel Ades, Emmanuel Raffoux, Caroline Berthier, Zeina Dassouki

Journal: Blood 2015;125(22):3447-54

PMID: 25800051

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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.

Address: Department of Internal Medicine, Department of Experimental Pathology, Microbiology and Immunology, and.; Department of Internal Medicine, Department of Cell Biology, Anatomy and Physiological Sciences, American University of Beirut, Beirut, Lebanon;; 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.; Service d'Hématologie Clinique, and.; Service d'Hématologie Senior, Hôpital St. Louis, Paris, France; Service d'Hématologie Clinique, Hôpital Avicenne, Bobigny, France;; INSERM U938, and Service d'Hématologie, Hôpital St. Antoine, Paris, France; Université Pierre et Marie Curie, Paris, France;; ER045, Laboratory of Stem Cells, Department of Biology, Faculty of Sciences, Lebanese University, Beirut, Lebanon; and.; Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.

DOI: 10.1182/blood-2014-11-612416

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MeSH Terms: Aged, Aged, 80 and over, Apoptosis, Arsenic Trioxide, Arsenicals, Cell Differentiation, Humans, Leukemia, Myeloid, Acute, Mutant Proteins, Mutation, Nuclear Proteins, Nucleophosmin, Oxides, Proteolysis, Tretinoin, Tumor Cells, Cultured