title: Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells.
abstract: Nucleophosmin (NPM1) mutations represent an attractive therapeutic target in acute myeloid leukemia (AML) because they are common (∼30% AML), stable, and behave as a founder genetic lesion. Oncoprotein targeting can be a successful strategy to treat AML, as proved in acute promyelocytic leukemia by treatment with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO), which degrade the promyelocytic leukemia (PML)-retinoic acid receptor fusion protein. Adjunct of ATRA to chemotherapy was reported to be beneficial for NPM1-mutated AML patients. Leukemic cells with NPM1 mutation also showed sensibility to ATO in vitro. Here, we explore the mechanisms underlying these observations and show that ATO/ATRA induce proteasome-dependent degradation of NPM1 leukemic protein and apoptosis in NPM1-mutated AML cell lines and primary patients' cells. We also show that PML intracellular distribution is altered in NPM1-mutated AML cells and reverted by arsenic through oxidative stress induction. Interestingly, similarly to what was described for PML, oxidative stress also mediates ATO-induced degradation of the NPM1 mutant oncoprotein. Strikingly, NPM1 mutant downregulation by ATO/ATRA was shown to potentiate response to the anthracyclin daunorubicin. These findings provide experimental evidence for further exploring ATO/ATRA in preclinical NPM1-mutated AML in vivo models and a rationale for exploiting these compounds in chemotherapeutic regimens in clinics.
authors: Institute of Hematology, Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, Perugia, Italy; and.
authors: Maria Paola
authors: MP
authors: Martelli
authors: Institute of Hematology, Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, Perugia, Italy; and.
authors: Ilaria
authors: I
authors: Gionfriddo
authors: Institute of Hematology, Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, Perugia, Italy; and.
authors: Federica
authors: F
authors: Mezzasoma
authors: Institute of Hematology, Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, Perugia, Italy; and.
authors: Francesca
authors: F
authors: Milano
authors: Institute of Hematology, Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, Perugia, Italy; and.
authors: Sara
authors: S
authors: Pierangeli
authors: Institute of Hematology, Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, Perugia, Italy; and.
authors: Floriana
authors: F
authors: Mulas
authors: Institute of Hematology, Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, Perugia, Italy; and.
authors: Roberta
authors: R
authors: Pacini
authors: Institute of Hematology, Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, Perugia, Italy; and.
authors: Alessia
authors: A
authors: Tabarrini
authors: Institute of Hematology, Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, Perugia, Italy; and.
authors: Valentina
authors: V
authors: Pettirossi
authors: Institute of Hematology, Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, Perugia, Italy; and.
authors: Roberta
authors: R
authors: Rossi
authors: Institute of Hematology, University of Catania, Catania, Italy.
authors: Calogero
authors: C
authors: Vetro
authors: Institute of Hematology, Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, Perugia, Italy; and.
authors: Lorenzo
authors: L
authors: Brunetti
authors: Institute of Hematology, Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, Perugia, Italy; and.
authors: Paolo
authors: P
authors: Sportoletti
authors: Institute of Hematology, Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, Perugia, Italy; and.
authors: Enrico
authors: E
authors: Tiacci
authors: Institute of Hematology, University of Catania, Catania, Italy.
authors: Francesco
authors: F
authors: Di Raimondo
authors: Institute of Hematology, Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, Perugia, Italy; and.
authors: Brunangelo
authors: B
authors: Falini
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D050505:Mutant Proteins / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism*; D000090243:Nucleophosmin; D015513:Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D001152:Arsenicals; D050505:Mutant Proteins; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D010087:Oxides; D000090243:Nucleophosmin; D014212:Tretinoin; D000077237:Arsenic Trioxide