Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells
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American Society of Hematology
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. © 2015 by The American Society of Hematology.
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Aged, Aged, 80 and over, Apoptosis, Arsenicals, Cell differentiation, Humans, Leukemia, myeloid, acute, Mutant proteins, Mutation, Nuclear proteins, Oxides, Proteolysis, Tretinoin, Tumor cells, cultured, Arsenic trioxide, Nucleophosmin, Retinoic acid, Mutant protein, Nuclear protein, Organoarsenic derivative, Oxide, Acute myeloblastic leukemia, Article, Cancer cell line, Clinical article, Drug potentiation, Gene, Gene mutation, Human, Human cell, Nucleolus, Nucleophosmin gene, Priority journal, Promyelocytic leukemia, Protein degradation, Protein localization, Drug effects, Genetics, Metabolism, Pathology, Tumor cell culture, Very elderly