Deneddylation of PML/RARα reconstructs functional PML nuclear bodies via orchestrating phase separation to eradicate APL

Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML/RAR alpha, which destroys the architecture of PML nuclear bodies (NBs). PML NBs are critical to tumor suppression, and their disruption mediated by PML/RAR alpha 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/RAR alpha. Mechanistically, PML/RAR alpha is neddylated in the RAR alpha 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/RAR alpha restores its phase separation process to reconstruct functional NBs and activates RAR alpha signaling, thereby suppressing PML/RAR alpha-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/RAR alpha-driven NB disruption and highlights targeting neddylation for APL eradication.

Automated summary

Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML/RAR alpha, which disrupts the construction of PML nuclear bodies (NBs). The disrupted NB assembly in APL is caused by neddylation-induced aberrant phase separation of PML/RAR alpha. Deneddylation restores the phase separation process, suppresses leukemogenesis, and can be targeted for APL eradication.