Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML/RARα, which destroys the architecture of PML nuclear bodies (NBs). PML NBs are critical to tumor suppression, and their disruption mediated by PML/RARα accelerates APL pathogenesis. However, the mechanisms of PML NB disruption remain elusive. Here, we reveal that the failure of NB assembly in APL results from neddylation-induced aberrant phase separation of PML/RARα. Mechanistically, PML/RARα is neddylated in the RARα moiety, and this neddylation enhances its DNA-binding ability and further impedes the phase separation of the PML moiety, consequently disrupting PML NB construction. Accordingly, deneddylation of PML/RARα restores its phase separation process to reconstruct functional NBs and activates RARα signaling, thereby suppressing PML/RARα-driven leukemogenesis. Pharmacological inhibition of neddylation by MLN4924 eradicates APL cells both in vitro and in vivo. Our work elucidates the neddylation-destroyed phase separation mechanism for PML/RARα-driven NB disruption and highlights targeting neddylation for APL eradication.

急性早幼粒细胞白血病 (APL) 是由癌蛋白 PML/RARα 驱动的，它会破坏 PML 核体 (NB) 的结构。PML NB 对肿瘤抑制至关重要，PML/RARα 介导的 PML NB 破坏会加速 APL 发病机制。然而，PML NB 破坏的机制仍然难以捉摸。在这里，我们揭示了 APL 中 NB 组装的失败是由 neddylation 诱导的 PML/RARα 异常相分离造成的。从机制上讲，PML/RARα 在 RARα 部分中被 neddylated，这种 neddylation 增强了其 DNA 结合能力，并进一步阻碍了 PML 部分的相分离，从而破坏了 PML NB 的构建。因此，PML/RARα 的去甲基化恢复其相分离过程以重建功能性 NB 并激活 RARα 信号传导，从而抑制 PML/RARα 驱动的白血病发生。MLN4924 对 neddylation 的药理学抑制可在体外和体内根除 APL 细胞。我们的工作阐明了 PML/RARα 驱动的 NB 破坏的 neddylation 破坏相分离机制，并强调了针对 APL 根除的 neddylation。