Common brain cancer mutation changes DNA shape to drive progression, exposing therapeutic target

UT MD Anderson Research News July 01, 2026

• Many gliomas have ATRX mutations that are linked to cancer progression, but how they drive disease progression was not entirely clear
• Researchers found that ATRX mutations reshape the DNA structure, creating new interactions that activate cancer-driving pathways, including the HOXA pathway
• Blocking HOXA signaling slowed ATRX-deficient tumor growth in preclinical models, highlighting a promising therapeutic strategy

A new study from researchers at The University of Texas MD Anderson Cancer Center has uncovered how one of the most common genetic alterations in glioma rewires the cancer cell genome to fuel tumor progression, suggesting a potential new therapeutic strategy for patients with ATRX-mutant gliomas.

The findings show that mutations in the ATRX gene fundamentally reprogram the epigenome and change the three-dimensional structure of chromatin, creating new interactions that activate developmental programs which tumors exploit to grow and spread. Targeting one of the genes downstream of ATRX in preclinical models – particularly in the HOXA family – slowed cancer progression.

The study, published in Nucleic Acids Research, was co-led by Jason Huse, M.D., Ph.D., professor of Anatomic Pathology, and Kunal Rai, Ph.D., professor of Genomic Medicine, with major contributions from Prit Benny Malgulwar, Ph.D., instructor of Translational Molecular Pathology, Anand Singh, Ph.D., senior research scientist in Genomic Medicine, and Ajay Saw, Ph.D., previous postdoctoral fellow in Genomic Medicine.

“ATRX mutations are a defining feature in many gliomas. Our findings show that losing ATRX doesn't just cause random damage but actually reprograms gene regulation architecture in ways that drive glioma formation and progression,” Huse said. “The next generation of personalized medicine will depend on integrating these genetic, epigenetic and structural components in order to identify the right treatment for the right patient at the right time.”

What is the role of ATRX in brain cancer?

The ATRX protein helps organize and regulate DNA. Mutations that inactivate ATRX disrupt DNA repair and allow cancer cells to multiply uncontrollably. ATRX mutations are a defining feature in several cancers, including gliomas. While researchers have known they are somehow involved in cancer development, it wasn’t clearly understood how they influence cell behavior.

The researchers found that ATRX-deficient cells change the DNA folding patterns and create new interactions in chromatin – the tightly packed complex of DNA, RNA and proteins that form chromosomes.

Reorganizing the structure of chromatin leads to the activation of new gene pathways that promote tumor progression. These pathways include WNT5A, which is linked to cancer cell movement and neurogenesis; SLITRK6, which is linked to cell migration and is linked to malignant brain tumors; and multiple HOXA genes that control spatial and temporal patterns in early brain development.

How could this finding be used to slow progression in ATRX-mutant tumors?

The researchers showed that blocking WNT5A or SLITRK6 slowed cancer cell movement in vitro. Additionally, targeting HOXA genes blocked tumor progression. The researchers tested a peptide called HXR9 to disrupt HOXA-mediated signaling, which led to cancer cell death, slowed tumor growth and extended survival in vivo.

“This study underscores the need to examine the functional consequences of genetic mutations rather than solely focusing on the mutations themselves,” Rai said. “These findings could also apply to ATRX mutations in other cancers and, on a larger level, epigenetic dysfunction reprograming cellular differentiation state and plasticity.”

Further clinical research is needed, but these results suggest that targeting the HOXA pathway could be a promising strategy for treating ATRX-deficient brain tumors and other ATRX-mutant cancer types. Current treatment options for many gliomas remain limited, and these new biomarkers and potential drug targets could help researchers and clinicians develop more precise therapies that can address ATRX deficiency.

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This study was funded by The Brockman Foundation, The Ivy Foundation, the National Institutes of Health, and institutional funding from UT MD Anderson. For a full list of collaborating authors, disclosures and funding sources, see the full paper in Nucleic Acids Research.