Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA.
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
Cell Rep. 2017 Oct 31;21(5):1267-1280. doi: 10.1016/j.celrep.2017.10.009.
Low-grade astrocytomas (LGAs) carry neomorphic mutations in isocitrate dehydrogenase (IDH) concurrently with P53 and ATRX loss. To model LGA formation, we introduced R132H IDH1, P53 shRNA, and ATRX shRNA into human neural stem cells (NSCs). These oncogenic hits blocked NSC differentiation, increased invasiveness in vivo, and led to a DNA methylation and transcriptional profile resembling IDH1 mutant human LGAs. The differentiation block was caused by transcriptional silencing of the transcription factor SOX2 secondary to disassociation of its promoter from a putative enhancer. This occurred because of reduced binding of the chromatin organizer CTCF to its DNA motifs and disrupted chromatin looping. Our human model of IDH mutant LGA formation implicates impaired NSC differentiation because of repression of SOX2 as an early driver of gliomagenesis.
低级别星形细胞瘤（LGAs）同时携带异柠檬酸脱氢酶（IDH）的新形式突变、P53 和 ATRX 缺失。为了模拟 LGA 的形成，我们将 R132H IDH1、P53 shRNA 和 ATRX shRNA 引入人神经干细胞（NSCs）中。这些致癌打击阻止了 NSC 的分化，增加了体内的侵袭性，并导致 DNA 甲基化和转录谱类似于 IDH1 突变的人类 LGAs。分化受阻是由于转录因子 SOX2 的启动子与其假定增强子分离，导致其转录沉默所致。这是由于染色质组织者 CTCF 与其 DNA 基序的结合减少，以及染色质环的破坏所致。我们的 IDH 突变型 LGA 形成的人类模型表明，由于 SOX2 的抑制导致 NSC 分化受损，可能是神经胶质瘤发生的早期驱动因素。
