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  • Low-grade Astrocytoma Core Mutations in IDH1, P53 and ATRX Cooperate to Block Differentiation of Human Neural Stem Cells via Epigenetic Repression of SOX2

    Final Number:
    1236

    Authors:
    Aram Modrek; Danielle Golub; Themasap Khan; Jod Prado; Chris Bowman; Jingjing Deng; Guoan Zhang; Pedro Rocha; Ramya Raviram; Harris Lazaris; James Stafford; Gary LeRoy; Michael Kader; Joravar Dhaliwal; Nermin Bayin; Joshua Frenster; Jonathan Serrano; Luis Chiriboga; Rabaa Baitalmal; Gouri Nanjangud; Andrew Chi; John Golfinos; Jing Wang; Matthias Karajannis; Richard Bonneau; Danny Reinberg; Aris Tsirigos; David Zagzag; Matija Snuderl; Jane Skok; Thomas Neubert; Dimitris Placantonakis

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2017 Annual Meeting

    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

    References:

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