(MEMPHIS, Tenn. – August 26, 2026 ) Scientists at St. Jude Children’s Research Hospital have shown that specific brain cells respond differently to the H3.3 K27M, a mutation in the histone H3.3 protein that drives many cases of diffuse midline glioma (DMG), depending on the cell’s location in the developing brain. These findings help explain why DMG, a pediatric brain cancer commonly associated with this mutation, typically arises in the brainstem and other midline regions. The study was published today in Nature Communications .
DMGs are childhood brain tumors that have no effective treatments. These tumors develop in midline structures of the central nervous system, such as the brainstem, thalamus and spinal cord, and are commonly characterized by H3.3 K27M mutations. While this mutation plays a critical role in DMG development, it was unclear why it leads to midline gliomas and not gliomas arising from other parts of the brain. Understanding this specificity is essential to understanding the biology of DMG.
“This mutation is fascinating because it can affect how DNA is packaged and interpreted in cells from every part of the body, yet it seems to have a selective advantage to drive cancer almost exclusively in the midline of the brain,” said corresponding author Suzanne Baker, PhD , St. Jude Comprehensive Cancer Center deputy director, Cancer Center Neurobiology and Brain Tumor Program co-leader, Center of Excellence in Neuro-Oncology Sciences (CENOS) member, and Department of Developmental Neurobiology member.
Location and intrinsic differences shape DMG formation
To explore these regional differences, the researchers examined oligodendrocyte precursor cells (OPCs) that mature to produce the cells that make myelin — the insulating material that helps nerve cells transmit signals efficiently. The scientists compared OPCs from two regions: one where H3.3 K27M-driven tumors frequently occur (the brainstem) and one where they rarely form (the telencephalon). By studying these cells under carefully controlled conditions, the team was able to track their development over time and their response to the mutation.
“By synchronizing differentiation in a controlled environment, we could examine the OPCs at various time points to identify baseline differences between the regions and to understand how the mutation influences these differences at a molecular level,” explained co-first author Jared Andrews, PhD, Department of Developmental Neurobiology.
The team found that H3.3 K27M alters DNA packaging in a similar manner across brain regions. However, the downstream consequences were strikingly different. In OPCs from the brainstem, the H3.3 K27M mutation kept cells in a more immature, actively dividing state for longer, unlike OPCs from other regions with the same mutation. This extended window of immaturity may help explain why the brainstem is particularly susceptible to DMG.
“It’s intriguing that a single mutation can induce similar widespread changes yet produce such region-specific effects in one part of the brain compared to another, even within the same cell type,” said Baker .
The team also found disruptions to signaling pathways which provide cues to guide cell identity and development. The H3.3 K27M mutation has a stronger impact on developmental signaling in brainstem OPCs than in OPCs from other regions, highlighting potential avenues for creating therapies tailored to treating this cancer.
“Understanding how pediatric cancers hijack normal developmental processes to drive tumor formation is key to improving treatments,” said Baker. “Findings in this study are relevant to many pediatric brain tumors, as the developmental stage of the brain plays an important role in the disease. Considering these factors is essential when designing effective therapies for childhood brain cancers.”
Authors and funding
The study’s other co-first authors are Chang-Hyuk Kwon, St. Jude; and Kaitlin Budd, formerly of St. Jude, now of Medpace. Other authors include Jon Larson, formerly of St. Jude, now of Sanford Burnham Prebys; and Abbas Shirinifard, Lawryn Kasper, Chanrika Williams, Alfonso Lavado, Sharon King, Jorge Gutierrez, Daniel Stabley, Tong Lin, Sara Lewis, Paul Northcott and Arzu Onar-Thomas, St. Jude.
The study was supported by grants from the NIH (P01CA096832, F31CA265285, P30CA21765), the St. Jude Transcription Collaborative, and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
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St. Jude Children's Research Hospital
St. Jude Children’s Research Hospital is leading the way the world understands, treats, and cures childhood catastrophic diseases. As the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children, St. Jude advances groundbreaking research and shares its discoveries worldwide to accelerate progress in pediatric medicine. Treatments developed at St. Jude have helped increase overall childhood cancer survival rates from 20% to more than 80% since the hospital opened more than 60 years ago. Through collaboration and innovation, St. Jude is working to ensure that children everywhere have access to the best possible care. To learn more, visit stjude.org , read St. Jude Progress, a digital magazine , and follow St. Jude on social media @stjuderesearch .
Nature Communications
26-Aug-2026