Precision post-translational modification of PML defines neuroblastoma clinical behaviour.
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BACKGROUND: Promyelocytic leukaemia protein (PML), a key regulator of nuclear architecture and cellular homeostasis, is increasingly recognised for its tumour-suppressive functions. In neuroblastoma (NBL), a clinically heterogeneous and aggressive paediatric malignancy, the prognostic role of PML and its post-translational modifications remains largely unexplored. METHODS: We investigated the prognostic and predictive significance of PML expression and its site-specific phosphorylation at serine 518 (S518) in a cohort of 121 NBL patients. Custom-synthesised antibodies and high-resolution tissue microarrays were used to quantitatively profile PML and pPML S518 expression via automated immunohistochemistry and digital image analysis. Survival outcomes were assessed using Kaplan-Meier and Cox regression analyses. Mechanistic insights were obtained using reverse‑engineered phospho‑mutant models enabling selective modulation of S518 phosphorylation. RESULTS: Our findings reveal a striking inverse relationship between PML abundance and S518 phosphorylation, with low PML and high pPML S518 strongly associated with advanced disease stage, metastasis, relapse, and therapy resistance. Survival analyses demonstrate that low PML predicts poor overall survival (OS), progression-free survival (PFS), and relapse-free survival (RFS), while elevated pPML S518 correlates with significantly worse outcomes across all endpoints. Multivariate Cox regression confirms both markers as independent predictors of survival. Mechanistically, reverse-engineered phospho-mutant models that enable selective switch-on/switch-off modulation of S518 phosphorylation demonstrated that phosphorylation at this site reduces PML abundance and promotes invasive cellular phenotype. CONCLUSION: PML loss and site-specific phosphorylation of PML at S518 represent robust prognostic and predictive biomarkers with potential utility in risk stratification. Targeting PML phosphorylation may offer a promising translational strategy to improve therapeutic efficacy in high‑risk NBL. KEY POINTS: PML depletion is a defining feature of aggressive neuroblastoma and is associated with advanced stage, metastasis and relapse. S518 phosphorylation emerges as the dominant post translational trigger committing PML to ubiquitin mediated degradation. High pPML S518 and low PML form a powerful prognostic axis that independently predicts OS, PFS, and RFS in neuroblastoma. PML loss and S518 phosphorylation define a molecular framework of heightened cellular plasticity underlying aggressive clinical behavior.