Atypical teratoid rhabdoid tumors (ATRTs) are challenging pediatric brain cancers that are predominantly associated with inactivation of the gene SMARCB1, a conserved subunit of the chromatin remodeling BAF complex, which has known contributions to developmental processes. To identify potential interactions between SMARCB1 loss and the process of neural development, we introduced an inducible SMARCB1 loss-of-function system into human induced pluripotent stem cells (iPSCs) that were subjected to either directed neuronal differentiation or differentiation into cerebral organoids. Using this system, we identified substantial differences in the downstream effects of SMARCB1 loss depending on differentiation state and identified an interaction between SMARCB1 loss and neural differentiation pressure that causes a resistance to terminal differentiation and a defect in maintenance of a normal cell state. Our results provide insight into how SMARCB1 loss might interact with neural development in the process of ATRT tumorigenesis.

中文翻译：

---

SMARCB1 损失与神经元分化状态相互作用以阻止成熟并影响细胞稳定性。

非典型畸胎样横纹肌样瘤 (ATRT) 正在挑战儿童脑癌，这些脑癌主要与 SMARCB1 基因失活有关，SMARCB1是染色质重塑 BAF 复合体的保守亚基，已知其对发育过程有贡献。为了确定 SMARCB1 损失与神经发育过程之间的潜在相互作用，我们引入了一种可诱导的SMARCB1功能丧失系统转化为人类诱导的多能干细胞 (iPSC)，这些细胞经过定向神经元分化或分化为大脑类器官。使用这个系统，我们根据分化状态确定了 SMARCB1 损失的下游影响的显着差异，并确定了 SMARCB1 损失和神经分化压力之间的相互作用，这种相互作用导致了对终末分化的抵抗和维持正常细胞状态的缺陷。我们的结果深入了解了 SMARCB1 缺失如何与 ATRT 肿瘤发生过程中的神经发育相互作用。