Proposed model of ATRA/ATO actions in NPM1-mutant cells. Mutant NPM1 leads to delocalization of both mutant (mt) and wild-type (wt) NPM1 (ie, from their normal nucleolar distribution to the cytoplasm). NPM1 mutation also results in disorganization of PML nuclear bodies (PML-NB), manifested by small size, heterogeneous appearance, nucleoplasmic localization, and dissociation from SUMO-1. These events, through mechanisms that have yet to be determined, disrupt both cell differentiation and apoptosis, contributing to leukemogenesis. Exposure of mutant NPM1-expressing cells to ATRA + ATO triggers pronounced oxidative stress and p53 activation, culminating in mutant NPM1 degradation. The loss of mutant NPM1 leads in turn to re-localization of wt NPM1 to the nucleolus, accompanied by reversal of PML-NB disorganization (eg, reflected by larger size, more homogeneous appearance, and restoration of the SUMO-1 association). These events culminate in leukemic cell differentiation and/or cell death. Professional illustration by Luk Cox, Somersault18:24.