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

Abstract

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.

How to manage acute promyelocytic leukemia

“…Indeed, PML --RARa represents the direct pharmaceutical target of two effective agents for APL, ATRA and ATO (Figure 1a). Arsenic binds to the RBCC domain of PML moiety, 24,25 whereas ATRA targets the RARa moiety of PML --RARa. Both the agents can induce the degradation of PML --RARa, 26 --29 which probably accounts for their curable effects.…”

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

“…APL is caused by the expression of PML/RARA, a protein resulting from the fusion of PML, a redox-sensing protein that organizes nuclear domains, with RARA (43)(44)(45)(46)(47). APL has drawn much attention because of its exquisite sensitivity to RA, which induces APL cell differentiation in vivo or ex vivo.…”

(+)α-Tocopheryl succinate inhibits the mitochondrial respiratory chain complex I and is as effective as arsenic trioxide or ATRA against acute promyelocytic leukemia in vivo

“…8 Indeed, the exquisite sensitivity of APL to ATO treatment has been recently demonstrated to be mediated by PML-RARa oxidation and subsequent degradation in an ROS-dependent process. 9 Interestingly, Weber et al 10 demonstrated that p0 cells that lack mitochondrial respiratory chain (MRC) activity are insensitive to a-TOS toxicity. However, few data are available regarding the early molecular events underlying this action.…”