Journal
BLOOD
Volume 125, Issue 22, Pages 3447-3454Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-11-612416
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Funding
- Beirut Laboratory - American University of Beirut Medical Practice Plan
- Beirut Laboratory - University Research Board
- Beirut Laboratory - Lebanese National Council for Scientific Research, and ERC (StemAPL grant)
- Paris Laboratory - INSERM
- Paris Laboratory - CNRS
- Paris Laboratory - Universite Paris-Diderot
- Paris Laboratory - Institut Universitaire de France
- Paris Laboratory - Ligue Contre le Cancer
- Paris Laboratory - Institut National du Cancer
- Paris Laboratory - French National Research Agency (ANR) Investissements d'Avenir program [ANR-11-PHUC-002, ANR-10-IHUB-0002]
- Paris Laboratory - Association pour la Recherche contre le Cancer (Griffuel Award)
- Paris Laboratory - Canceropole Ile de France
- Paris Laboratory - European Research Council (STEMAPL advanced grant)
- Fondation pour la Recherche Medicale (U.S.)
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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.
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