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Cancer Cell. 2010 Jul 13;18(1):88-98. doi: 10.1016/j.ccr.2010.06.003.

PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3.

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Inserm/Centre National de la Recherche Scientifique (CNRS)/Université Paris Diderot/Institut Universitaire Hématologie U944/UMR7212, Laboratoire associé de la Ligue Nationale contre le Cancer, Hôpital St Louis, 1, Av. C. Vellefaux, 75475 Paris, Cedex 10, France.


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.

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