神经母细胞瘤是儿童最常见的颅外实性肿瘤。高危患者的一个亚组以编码由35个外显子组成的染色质重塑因子ATRX的异常为特征。与其他小儿癌症中ATRX点突变最为频繁不同，多外显子缺失（MEDs）是神经母细胞瘤中ATRX异常最常见的类型。这些MEDs中有75%被预测能够产生同框融合蛋白，相对于无意义突变，这表明可能具有增益功能效应。对于神经母细胞瘤，只有少数患者衍生的ATRX异常模型。因此，我们在几种神经母细胞瘤细胞系和一个肿瘤球中使用CRISPR-Cas9创造了等基因ATRX异常模型，并对这些模型和患者衍生模型进行了全RNA测序。基因集富集分析（GSEA）显示，在我们的等基因ATRX外显子2-10 MED模型系统、患者来源的MED模型和包含两个ATRX外显子2-10 MED患者样本的肿瘤数据中，与核糖体生物合成和几个代谢过程有关的基因表达减少。而在我们的等基因ATRX敲除和外显子2-13 MED模型中，这些相同过程表现出增加的表达。我们的验证证实了ATRX在核糖体稳态调节中的作用。我们确定的ATRX异常神经母细胞瘤中的这两种不同的分子表达模式，可能需要不同的治疗方案。版权声明：© 2023 van Gerven等。本文为开放获取文章，根据知识共享署名许可协议，任何人在保留原始作者和来源的情况下，均可自由使用、分发和复制本文。

Neuroblastoma is the most common extracranial solid tumor in children. A subgroup of high-risk patients is characterized by aberrations in the chromatin remodeller ATRX that is encoded by 35 exons. In contrast to other pediatric cancer where ATRX point mutations are most frequent, multi-exon deletions (MEDs) are the most frequent type of ATRX aberrations in neuroblastoma. 75% of these MEDs are predicted to produce in-frame fusion proteins, suggesting a potential gain-of-function effect compared to nonsense mutations. For neuroblastoma there are only a few patient-derived ATRX aberrant models. Therefore, we created isogenic ATRX aberrant models using CRISPR-Cas9 in several neuroblastoma cell lines and one tumoroid and performed total RNA-sequencing on these and the patient-derived models. Gene set enrichment analysis (GSEA) showed decreased expression of genes related to both ribosome biogenesis and several metabolic processes in our isogenic ATRX exon 2-10 MED model systems, the patient-derived MED models and in tumor data containing two patients with an ATRX exon 2-10 MED. In sharp contrast, these same processes showed an increased expression in our isogenic ATRX knock-out and exon 2-13 MED models. Our validations confirmed a role of ATRX in the regulation of ribosome homeostasis. The two distinct molecular expression patterns within ATRX aberrant neuroblastomas that we identified imply that there might be a need for distinct treatment regimens.Copyright: © 2023 van Gerven et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.