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This research investigates how ATRX loss and mutations affect developmental pathways in pediatric gliomas.

June 26, 2026Open Access

ID #304 Molecular hijacking of developmental master regulators through BRD4-driven super-enhancers in pediatric and AYA gliomas

AMAnnette MachadoThe University of Texas MD Anderson Cancer Center PMPrit MalgulwarThe University of Texas MD Anderson Cancer Center DLDung‐Fang LeeThe University of Texas Health Science Center at Houston

Key Points

This research investigates how ATRX loss and mutations affect developmental pathways in pediatric gliomas.
Developed isogenic neural stem cell models with ATRX-deficient glioma variants
Conducted integrated epigenomic and transcriptomic profiling
Performed H3K27ac analysis across glioma datasets
ATRX deficiency activates SOX2, SOX4, and POU3F2 via BRD4-occupied super-enhancers
Identified core regulatory circuits specific to glioma subtypes
ATRX-deficient models showed selective sensitivity to BRD4 inhibition (IC50 = 0.2 μM)

Abstract

Abstract Pediatric and adolescent/young adult (AYA) gliomas remain among the deadliest childhood cancers. Key subtypes include H3.3 G34R/V diffuse hemispheric glioma (DHG), IDH-mutant gliomas, and H3 K27M diffuse midline gliomas (DMG), with ATRX loss occurring at a high frequency in DHG and IDH-mutant tumors (80-90%), but less frequently in DMG (15-30%). While these aggressive tumor types each exhibit stalled neurodevelopmental programs as a central feature of their respective pathogeneses, the molecular mechanisms by which ATRX deficiency and associated mutations in either H3.3 or IDH1/2 drive this developmental dysregulation remain unknown. We hypothesize that the epigenomic consequences of these combined molecular alterations effectively hijack master transcriptional regulators to induce and maintain aberrant neuro-progenitor states. Using isogenic neural stem cell (NSC) models harboring the defining alterations of ATRX-deficient glioma variants, along with integrated epigenomic and transcriptomic profiling, we discovered that ATRX deficiency activates transcription of SOX2, SOX4, and POU3F2 through the formation of BRD4-occupied super-enhancers. Furthermore, loss of repressive epigenetic marks in these models allows aberrant enhancer accessibility at specific neuroprogenitor gene loci. Integrative H3K27ac analysis of pediatric and adult glioma datasets DHG, n = 10; DMG, n = 5; GBM, n = 4 validated these master regulators and identified subtype-specific core regulatory circuits (CRCs): autoregulatory transcriptional networks that sustain oncogenic neuro-progenitor identity. Notably, ATRX-deficient models and patient-derived cell lines showed a selective sensitivity to BRD4 inhibition (IC50 = 0.2 μM vs. 0.8 μM in ATRX-WT), strongly suggesting that this biology could be targeted therapeutically. These findings reveal ATRX loss as a key epigenetic driver that engages developmental master regulators and their respective CRCs through super-enhancer remodeling, establishing a novel therapeutic vulnerability in pediatric and AYA gliomas.

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