Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells
Maria Paola Martelli, Ilaria Gionfriddo, Federica Mezzasoma, Francesca Milano, Sara Pierangeli, Floriana Mulas, Roberta Pacini, Alessia Tabarrini, Valentina Pettirossi, Roberta Rossi, Calogero Vetro, Lorenzo Brunetti, Paolo Sportoletti, Enrico Tiacci, Francesco Di Raimondo, Brunangelo Falini, Maria Paola Martelli, Ilaria Gionfriddo, Federica Mezzasoma, Francesca Milano, Sara Pierangeli, Floriana Mulas, Roberta Pacini, Alessia Tabarrini, Valentina Pettirossi, Roberta Rossi, Calogero Vetro, Lorenzo Brunetti, Paolo Sportoletti, Enrico Tiacci, Francesco Di Raimondo, Brunangelo Falini
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.
© 2015 by The American Society of Hematology.
Source: PubMed