Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells
Hiba El Hajj, Zeina Dassouki, Caroline Berthier, Emmanuel Raffoux, Lionel Ades, Olivier Legrand, Rita Hleihel, Umut Sahin, Nadim Tawil, Ala Salameh, Kazem Zibara, Nadine Darwiche, Mohamad Mohty, Hervé Dombret, Pierre Fenaux, Hugues de Thé, Ali Bazarbachi, Hiba El Hajj, Zeina Dassouki, Caroline Berthier, Emmanuel Raffoux, Lionel Ades, Olivier Legrand, Rita Hleihel, Umut Sahin, Nadim Tawil, Ala Salameh, Kazem Zibara, Nadine Darwiche, Mohamad Mohty, Hervé Dombret, Pierre Fenaux, Hugues de Thé, Ali Bazarbachi
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.
Source: PubMed