High-risk neuroblastoma remains a major clinical challenge, with a five-year survival rate below 50% despite intensive multimodal therapies. MYCN amplification, a hallmark of high-risk disease, drives an aggressive transcriptional program that maintains undifferentiated and proliferative states in neuroblastoma cells. Given its central role in oncogenic transcription, MYCN represents an attractive therapeutic target; however, its undruggable nature has prompted efforts to identify upstream regulators or cofactors that sustain MYCN expression and oncogenic function. In this study, we investigate the role of the cohesin loading factor NIPBL in supporting the MYCN-driven transcriptional program. We demonstrate that elevated NIPBL expression is associated with undifferentiated, proliferative neuroblastoma cell states and poor clinical outcomes in neuroblastoma patients. Functionally, NIPBL depletion reduces MYCN mRNA and protein levels and induces widespread transcriptional reprogramming consistent with neuronal differentiation. These transcriptional changes are accompanied by decreased neuroblastoma cell proliferation and increased neuronal differentiation, reflecting impaired regulation of MYCN target genes upon NIPBL loss. Collectively, we have established a mechanistic link between NIPBL and the MYCN-driven transcriptome, highlighting NIPBL as a potential therapeutic vulnerability to promote differentiation in high-risk neuroblastoma.
高危神经母细胞瘤仍是临床治疗的主要挑战，即使采用强化多模式治疗方案，其五年生存率仍低于50%。MYCN扩增作为高危疾病的重要标志，驱动着侵袭性转录程序，维持神经母细胞瘤细胞的未分化与增殖状态。鉴于其在致癌转录中的核心作用，MYCN成为极具吸引力的治疗靶点；然而，其"不可成药"特性促使研究转向寻找维持MYCN表达及致癌功能的上游调控因子或辅助因子。本研究聚焦于黏连蛋白装载因子NIPBL在支持MYCN驱动转录程序中的作用。我们发现NIPBL高表达与神经母细胞瘤细胞的未分化、增殖状态及患者不良临床预后密切相关。功能实验表明，敲低NIPBL可降低MYCN mRNA及蛋白水平，并引发与神经元分化相一致的广泛转录重编程。这些转录变化伴随着神经母细胞瘤细胞增殖减弱和神经元分化增强，反映了NIPBL缺失导致MYCN靶基因调控受损。本研究系统阐明了NIPBL与MYCN驱动转录组之间的机制关联，提示NIPBL可能成为促进高危神经母细胞瘤分化的潜在治疗靶点。
肿瘤(癌症)患者之家