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Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells.

Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells.

Authors :
Martelli MP
Gionfriddo I
Mezzasoma F
Milano F
Pierangeli S
Mulas F
Pacini R
Tabarrini A
Pettirossi V
Rossi R
Vetro C
Brunetti L
Sportoletti P
Tiacci E
Di Raimondo F
Falini B
Source :
Blood [Blood] 2015 May 28; Vol. 125 (22), pp. 3455-65. Date of Electronic Publication: 2015 Mar 20.
Publication Year :
2015

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.<br /> (© 2015 by The American Society of Hematology.)

Details

Language :
English
ISSN :
1528-0020
Volume :
125
Issue :
22
Database :
MEDLINE
Journal :
Blood
Publication Type :
Academic Journal
Accession number :
25795919
Full Text :
https://doi.org/10.1182/blood-2014-11-611459