Glioblastomas exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a large subset of patient-derived glioblastoma stem cells (GSCs) express high levels of Achaete-scute homolog 1 (ASCL1), a proneural transcription factor involved in normal neurogenesis. ASCL1^hi GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1^lo GSCs do not. Increasing ASCL1 levels in ASCL1^lo GSCs restores neuronal lineage potential, promotes terminal differentiation, and attenuates tumorigenicity. ASCL1 mediates these effects by functioning as a pioneer factor at closed chromatin, opening new sites to activate a neurogenic gene expression program. Directing GSCs toward terminal differentiation may provide therapeutic applications for a subset of GBM patients and strongly supports efforts to restore differentiation potential in GBM and other cancers.

中文翻译：

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ASCL1重组染色质直接神经元命运，并抑制胶质母细胞瘤干细胞的致瘤性。

胶质母细胞瘤表现出分级的细胞结构，表明它们由保留部分但异常分化潜能的赘生性干细胞驱动。在这里，我们显示，大量的患者源性胶质母细胞瘤干细胞（GSC）表达高水平的Achaete-scute同源物1（ASCL1），这是参与正常神经发生的前神经转录因子。ASCL1 ^hi GSC对Notch信号的抑制具有潜在的终末神经元分化能力，而ASCL1 ^lo GSC没有。在ASCL1 ^lo中增加ASCL1级别GSCs恢复神经元谱系潜力，促进终末分化，并减弱致瘤性。ASCL1通过充当封闭染色质的先驱因子，打开新位点以激活神经原性基因表达程序来介导这些作用。将GSC引导至终末分化可能为部分GBM患者提供治疗应用，并大力支持恢复GBM和其他癌症分化潜能的努力。