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

Abstract

Key Points• ATRA and ATO affect NPM1 protein levels in AML cells and induce cell growth inhibition and apoptosis.• AML cells with mutated NPM1respond to ATRA/ATO, and this might be exploited therapeutically.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. (Blood. 2015;125(22):3455-3465)

Selective Toxicity of Investigational Ixazomib for Human Leukemia Cells Expressing Mutant Cytoplasmic NPM1: Role of Reactive Oxygen Species

“…4). Data from Falini and colleagues (6) further supported this finding by demonstrating growth inhibition and apoptosis in AML cells expressing mutated NPM1 after treatment with ATO alone and in combination with ATRA. This result is also supported by the recent observation that CD34 À AML cells, an immunophenotypic feature associated with AML expressing NPMc þ (2), are more sensitive to bortezomib treatment than are CD34 þ AML cells (7).…”

An update of current treatments for adult acute myeloid leukemia

“…More recently, preclinical studies of arsenic trioxide (ATO) in NPM1-mutated AML from 2 groups strongly suggested that ATO may have a beneficial effect in this subset. 70,71 Because extensive clinical experience with ATO has been gained in the therapy of APL, clinical studies are planned to confirm whether there is a beneficial role of ATO in the treatment of NPM1-mutated patients.…”

Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance

“…Examples of this would include the sensitivity of MLL-rearranged leukemias to BET, hDOT1L, and CDK6 inhibitors [78][79][80][81][82] ; of NPM1c leukemias to ATRA1ATO, 83,84 BET inhibitors, and selective inhibitors of nuclear export 85 ; and of IDH2 mutated leukemias to BCL-2 inhibitors. 86 In these associations, no mutation or transcriptional upregulation of the target is evident from molecular studies, however preclinical sensitivity has been demonstrated, with these associations currently being tested in early phase clinical trials.…”