Introduction: Low-grade astrocytomas (LGA) carry neomorphic mutations in Isocitrate Dehydrogenase (IDH), concurrently with P53 and ATRX loss. The molecular mechanisms underlying formation of LGA are not well understood.
Methods: To model LGA formation, we introduced R132H IDH1, P53 shRNA and ATRX shRNA in human neural stem cells (NSCs) derived from human embryonic stem cells.
Results: These oncogenic hits blocked NSC differentiation, increased invasiveness in vivo and led to an epigenetic and transcriptional profile resembling IDH1-mutant human LGAs. The differentiation block was caused by transcriptional silencing of transcription factor SOX2, secondary to disassociation of its promoter from a putative enhancer. This occurred due to reduced binding of the chromatin organizer CTCF to its DNA motifs and disrupted chromatin looping.
Conclusions: Our human model of IDH-mutant LGA implicates impaired NSC differentiation due to epigenetic repression of SOX2 as an early driver of gliomagenesis. This model can serve as a platform for understanding human gliomagenesis and testing new therapies.
Patient Care: Improved mechanistic understanding of low-grade glioma formation.
Learning Objectives: 1) To understand the main genetic alterations found in low-grade astrocytoma
2) To understand epigenetic mechanisms that may underlie astrocytoma formation