NEDDylation Of PML/RARα Regulates The Assembly Of PML Nuclear Bodies And Its Function In Acute Promyelocytic Leukemia

PML/RARα oncoprotein is the driver factor to initiate acute promyelocytic leukemia(APL),which destroys the architecture of PML nuclear bodies(NBs).PML NBs are critical to tumor suppression and the disruption mediated by PML/RARα accelerates APL pathogenesis.However,the mechanism of NB disruption remains elusive.Here,we systematically reveal the mechanism and molecular process which account for PML NB disruption by PML/RARα in APL.At first,we identified that NEDDylation inhibitors could induce PML/RARα to reassemble functional NB structures.Mechanically,PML/RARα was NEDDylated in the RARa moiety.Based on the confirmation that PML assembled into NB structures by liquid-liquid phase separation(LLPS),we found that NEDDylation modification enhanced the DNA-binding ability of PML/RARα and further impeded its phase separation ability,consequently disrupting PML NB construction.Importantly,de NEDDylation of PML/RARα restored its LLPS process to reconstruct functional NBs,thereby suppressing the PML/RARα-driven leukemogenesis.Pharmacological inhibition of NEDDylation by MLN4924 eradicated APL cells both in vitro and in vivo.Herein,our work not only elucidates the NEDDylation-destroyed LLPS mechanism for PML/RARα-driven NB disruption,but highlights “targeting NEDDylation to reconstruct NBs” as the novel strategy for APL eradication and overcoming APL resistance.