Kang Jee-Youn, Tremble Kaitlyn A, Homan Philip, Thiele Carol J
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
CCR Collaborative Bioinformatics Resource, National Cancer Institute, Bethesda, MD 20892, USA.
Cancers (Basel). 2025 Aug 9;17(16):2615. doi: 10.3390/cancers17162615.
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然是一个重大的临床挑战，尽管采用了强化多模式疗法，其五年生存率仍低于50%。MYCN扩增是高危疾病的一个标志，它驱动着一个激进的转录程序，维持神经母细胞瘤细胞的未分化和增殖状态。鉴于其在致癌转录中的核心作用，MYCN是一个有吸引力的治疗靶点；然而，其难以靶向的特性促使人们努力寻找维持MYCN表达和致癌功能的上游调节因子或辅助因子。在本研究中，我们研究了黏连蛋白装载因子NIPBL在支持MYCN驱动的转录程序中的作用。我们证明，NIPBL表达升高与未分化、增殖性神经母细胞瘤细胞状态以及神经母细胞瘤患者的不良临床结果相关。在功能上，NIPBL缺失会降低MYCN mRNA和蛋白水平，并诱导与神经元分化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少和神经元分化增加，反映出NIPBL缺失后MYCN靶基因的调控受损。总体而言，我们已经建立了NIPBL与MYCN驱动的转录组之间的机制联系，突出了NIPBL作为促进高危神经母细胞瘤分化的潜在治疗靶点。
