Precision post-translational modification of PML defines neuroblastoma clinical behaviour

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2026-08-18 DOI:10.1002/ctm2.70763

Sreenidhi Mohanvelu, Poorvi Subramanian, Sheeja Aravindan, Madhi Oli Ramamurthy, Sivaroopan Aravindan, Afsana Parveen Jahir Hussain, Natarajan Aravindan

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引用次数: 0

Abstract

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.

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PML的精确翻译后修饰定义了神经母细胞瘤的临床行为

早幼粒细胞白血病蛋白（PML）是核结构和细胞稳态的关键调节因子，其肿瘤抑制功能越来越被人们所认识。神经母细胞瘤（NBL）是一种临床异质性和侵袭性的儿科恶性肿瘤，PML及其翻译后修饰的预后作用在很大程度上仍未被探索。方法研究121例NBL患者PML表达及其518丝氨酸位点特异性磷酸化（S518）对预后的预测意义。通过自动免疫组织化学和数字图像分析，使用定制合成抗体和高分辨率组织微阵列定量分析PML和pPML S518的表达。采用Kaplan-Meier和Cox回归分析评估生存结果。利用反向工程磷酸化突变模型获得了对S518磷酸化选择性调节的机制见解。结果PML丰度与S518磷酸化呈显著的负相关，低PML和高pPML S518与疾病晚期、转移、复发和治疗抵抗密切相关。生存分析表明，低PML预测较差的总生存期（OS）、无进展生存期（PFS）和无复发生存期（RFS），而pPML S518升高与所有终点的显著较差结果相关。多变量Cox回归证实了这两种标记都是独立的生存预测因子。机制上，能够选择性开启/关闭S518磷酸化调节的反向工程磷酸化突变模型表明，该位点的磷酸化降低了PML丰度并促进了侵袭性细胞表型。结论PML丢失和PML在S518位点特异性磷酸化是可靠的预后和预测性生物标志物，在风险分层中具有潜在的应用价值。靶向PML磷酸化可能为提高高风险NBL的治疗效果提供了一种有希望的转化策略。PML耗竭是侵袭性神经母细胞瘤的一个决定性特征，与晚期、转移和复发有关。S518磷酸化是翻译后PML发生泛素介导降解的主要触发因素。高pPML S518和低PML形成一个强大的预后轴，独立预测神经母细胞瘤的OS、PFS和RFS。PML缺失和S518磷酸化定义了细胞可塑性增强的分子框架，这是侵略性临床行为的基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.