PML核体（NBs）在PML-RARA驱动的急性早幼粒细胞白血病（APL）中受到破坏。三氧化砷（ATO）治愈了70％的APL患者，促使PML-RARA降解和NB重组。在非APL细胞中，砷结合到PML上也会增强NB的形成。然而，涉及的实际分子机制仍然不明确。在这里，我们确定了PML NBs显示液-液相分离的某些特征，ATO诱导了一种凝胶状转变。PML B-box-2结构显示α螺旋驱动B2三聚体化，并定位一个半胱氨酸三联体，形成一个理想的砷结合口袋。更改后者之一会阻碍ATO驱动的NB组装、PML泛素化和PML-RARA降解，从机制上解释了临床ATO耐药性。这个B2三聚体和C213三联体创建了一个对氧化敏感的可变电阻器，能够控制PML NB组装动力学以及基础状态和应激反应期间的下游信号传导。这些发现确定了砷靶向PML的结构基础，为开发新的抗癌药物铺平了道路。

PML Nuclear Bodies (NBs) are disrupted in PML-RARA-driven acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) cures 70% APL patients, driving PML-RARA degradation and NB reformation. In non-APL cells, arsenic binding onto PML also amplifies NB formation. Yet, the actual molecular mechanism(s) involved remain(s) elusive. Here, we establish that PML NBs display some features of liquid-liquid phase separation and that ATO induces a gel-like transition. PML B-box-2 structure reveals an alpha helix driving B2 trimerization and positioning a cysteine trio to form an ideal arsenic-binding pocket. Altering either of the latter impedes ATO-driven NB-assembly, PML sumoylation and PML-RARA degradation, mechanistically explaining clinical ATO-resistance. This B2 trimer and the C213 trio create an oxidation-sensitive rheostat that controls PML NB assembly dynamics and downstream signaling in both basal state and during stress response. These findings identify the structural basis for arsenic targeting of PML which could pave the way to novel cancer drugs.