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Modeling Astrocytoma Pathogenesis In Vitro and In Vivo Using Cortical Astrocytes or Neural Stem Cells from Conditional, Genetically Engineered Mice
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ATRX inactivation disrupts global chromatin state and topology to dysregulate neurodevelopmental pathways in glioma

Prit Benny Malgulwar1, Anand Singh2, Ajay Kumar Saw2

  • 1Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.

Nucleic Acids Research
|June 24, 2026
PubMed

Insights

Loss of the ATRX gene alters chromatin structure, impacting neurodevelopmental genes and promoting glioma growth. Targeting HOXA-PBX binding offers a potential therapeutic strategy for ATRX-deficient cancers.

Area of Science:

  • Genomics
  • Epigenetics
  • Cancer Biology

Background:

  • Mutational inactivation of ATRX (alpha-thalassemia mental retardation X-linked) is common in many cancers.
  • ATRX deficiency affects chromatin landscapes, altering cell differentiation and cancer-related phenotypes, especially in neuroepithelial and mesenchymal cells.

Purpose of the Study:

  • To comprehensively define ATRX-deficient epigenomic abnormalities.
  • To investigate the transcriptional and phenotypic consequences of ATRX loss in a disease-relevant context.

Main Methods:

  • High-throughput epigenome mapping in isogenic Atrx- and Atrx+ murine neuroepithelial progenitors (mNPCs).
  • Analysis of 3D chromatin architecture, topologically associating domains (TADs), and CCCTC-binding factor binding sites.
  • Pharmacologic inhibition of HOXA-PBX binding.

Main Results:

  • ATRX loss significantly impacts 3D chromatin architecture and looping, altering TADs and CCCTC-binding factor sites.
  • Disrupted chromatin topology affects neurodevelopmental genes, including Slitrk6 and the HoxA cluster.
  • Targeting HOXA-PBX binding selectively inhibited the in vivo growth of patient-derived ATRX-deficient glioma stem cells.

Conclusions:

  • Rewiring of chromatin topology and heterochromatin structure in ATRX-deficient cells promotes cancer-associated phenotypes.
  • Therapeutic targeting of neurodevelopmental gene expression is a viable strategy for ATRX-deficient gliomas.

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