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

Xuejing Shao, Yingqian Chen, Aixiao Xu, Danyan Xiang, Wei Wang, Wenxin Du, Yunpeng Huang, Xingya Zhang, Minyi Cai, Zhimei Xia, Yi Wang, Ji Cao, Yan Zhang, Bo Yang, Qiaojun He, Meidan Ying

Cell death and differentiation 2022 Aug

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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. © 2022. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.

Citation

Xuejing Shao, Yingqian Chen, Aixiao Xu, Danyan Xiang, Wei Wang, Wenxin Du, Yunpeng Huang, Xingya Zhang, Minyi Cai, Zhimei Xia, Yi Wang, Ji Cao, Yan Zhang, Bo Yang, Qiaojun He, Meidan Ying. Deneddylation of PML/RARα reconstructs functional PML nuclear bodies via orchestrating phase separation to eradicate APL. Cell death and differentiation. 2022 Aug;29(8):1654-1668