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.
Cancer Cell. 2010 Jul 13;18(1):88-98. doi: 10.1016/j.ccr.2010.06.003.
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.
砷剂通过对 PML/RARA 癌蛋白的泛素化使其降解，从而治疗急性早幼粒细胞白血病（APL）。然而，砷剂如何引发 PML 的泛素化在很大程度上仍未得到解释。砷剂结合相邻的半胱氨酸并增加活性氧（ROS）的产生。我们证明，在砷剂暴露后，PML 发生 ROS 引发的分子间二硫键形成，并直接与砷结合。形成二硫键的 PML 或 PML/RARA 多聚体形成与核基质相关的核小体（NBs），发生泛素化并被降解。由与砷剂结合的 PML/RARA 突变体转化的造血祖细胞表现出对砷剂反应的缺陷。相反，非砷氧化剂在体内引发 PML/RARA 多聚体化、NB 相关、降解和白血病反应，但不影响 PLZF/RARA 驱动的 APL。因此，PML 的氧化调节 NB 的生物发生，而氧化增强的 PML/RARA 多聚化和直接的砷结合共同增强 APL 对砷剂的敏感性。
