PML/RARA Oxidation and Arsenic Binding Initiate the Antileukemia Response of As2O3

As2O3 cures acute promyelocytic leukemia (APL) by initiating PML/RARA oncoprotein degradation, through sumoylation of its PML moiety. However, how As2O3 initiates PML sumoylation has remained largely unexplained. As2O3 binds vicinal cysteines and increases reactive oxygen species (ROS) production. We demonstrate that upon As2O3 exposure, PML undergoes ROS-initiated intermolecular disulfide formation and binds arsenic directly. Disulfide-linked PML or PML/RARA multimers form nuclear matrix-associated nuclear bodies (NBs), become sumoylated and are degraded. Hematopoietic progenitors transformed by an As2O3-binding PML/RARA mutant exhibit defective As2O3 response. Conversely, nonarsenical oxidants elicit PML/RARA multimerization, NB-association, degradation, and leukemia response in vivo, but do not affect PLZF/RARA-driven APLs. Thus, PML oxidation regulates NB-biogenesis, while oxidation-enforced PML/RARA multimerization and direct arsenic-binding cooperate to enforce APL's exquisite As2O3 sensitivity.