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

Summary As 2 O 3 cures acute promyelocytic leukemia (APL) by initiating PML/RARA oncoprotein degradation, through sumoylation of its PML moiety. However, how As 2 O 3 initiates PML sumoylation has remained largely unexplained. As 2 O 3 binds vicinal cysteines and increases reactive oxygen species (ROS) production. We demonstrate that upon As 2 O 3 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 As 2 O 3 -binding PML/RARA mutant exhibit defective As 2 O 3 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 As 2 O 3 sensitivity.