STEM-27. TRACING THE ORIGINS OF H3.3K27M MUTANT DIFFUSE MIDLINE GLIOMA
Bibliographic record
Abstract
Abstract Diffuse midline gliomas (DMGs) are universally fatal pediatric brain tumours defined by their midline localization, early onset, and distinct mutational landscape. The H3.3K27M mutation is found in approximately 80% of DMGs, marking it as a key initiating event. However, H3.3K27M alone does not induce brain tumour formation in experimental models, suggesting that its oncogenic potential may be linked to specific developmental windows and susceptible precursor populations. Identifying the cellular states that are vulnerable to transformation is critical to understanding DMG initiation. To establish a reference framework for these vulnerable states, we generated a single-cell RNA sequencing atlas of normal hindbrain development. Using a Sox2-eGFP reporter mouse and FACS-based enrichment of Sox2+ precursors, we profiled over 120,000 cells across ten developmental stages, capturing critical transitions in neurogenesis and gliogenesis. To reveal regional differences, we integrated the atlas with a similarly generated forebrain atlas, providing a comprehensive map of neurodevelopmental trajectories where DMG mutations might exert their effects. Building on this developmental reference, we utilized inducible mouse models to introduce H3.3K27M mutations in precursors and employ lineage tracing to track their fate over time. When combined with loss of Trp53 and overexpression of PDGFRa, alterations prevalent in DMG, mice develop tumours that resemble the human disease. H3.3K27M-driven tumours consistently localize to the pons, in contrast to H3 wild-type tumours, which occur more variably across the forebrain and hindbrain. Tracking these pontine tumours using serial MRI revealed that tumours arise well before symptom onset and exhibit growth dynamics that vary by location and timing. Earlier-arising tumours are more aggressive and tend to occur in posterior locations. Together, our integrated approach combining lineage tracing, tumour modelling, and a developmental atlas provides a powerful platform to dissect the early events in DMG pathogenesis and identify developmental vulnerabilities that may be targeted for early intervention.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".