Abstract A35: From map to model: Genetic evolution of diffuse intrinsic pontine glioma provides the framework for accurate tumor modeling
Bibliographic record
Abstract
Abstract Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric high-grade glioma (HGG) that diffusely penetrates the brainstem and is the leading cause of pediatric brain tumor death. Around 80% of DIPGs harbor lysine 27-methionine (K27M) substitutions in histone H3. H3K27M inhibits the activity of Polycomb repressive complex 2 (PRC2) that deposits H3K27me3, leading to widespread H3K27me3 loss, but how this leads to cancer is unclear. Further, despite clonal analysis indicating that H3K27M is the tumor-initiating mutation in DIPG, in vivo models of H3K27M-driven cancer have failed to generate tumors without additional oncogenic drivers. Thus, the early events driven by H3K27M alone remain obscure as does the most relevant cell of origin. To address the role of H3K27M in tumor initiation we generated a transgenic murine model with a tetracycline-repressible, Cre-inducible H3F3A-K27M transgene within the ROSA26 locus. This allows for both spatial and temporal control of K27M expression, via the cre-inducible LSL cassette and tetracycline treatment, respectively. These mice were crossed with the brain specific -cre drivers Nestin-, Olig2-, or GFAP-, targeting neural stem cells, oligodendrocyte progenitor cells, and glial progenitor cells, respectively. H3F3A K27M/-cre double-positive mice were born significantly below mendelian ratios, the most severe being those crossed with Olig2-cre (Nestin- 18/100; 0.18, GFAP- 15/114; 0.132, Olig2- 9/106; 0.08). All mice displayed a degree of ataxia and a smaller overall stature compared to littermate controls, with the most severe phenotype being particularly evident in Olig2-cre mice. Additionally, both Nestin- and GFAP-cre crosses experienced decreased survival post-weaning age (p21) (Nestin- 13/18 alive, GFAP- 10/15 alive); however, this decrease was greatly exaggerated in Olig2-cre (1/9 alive). Together, these data suggest that the displayed phenotypes are dependent upon the cell population in which H3F3A K27M is expressed. We also found that in addition to spatial control, temporal control of H3F3A K27M expression is critical to survival. Doxycycline (dox) was administered to breeding pairs for each H3F3A K27M/-cre line to repress transgene expression. Dox-H3F3A K27M/-cre double-positive mice were born at higher mendelian ratios than their no-dox counterparts (Nestin- 26/79; 0.33, GFAP- 14/50; 0.28, Olig2- 17/52; 0.327). Litters remained on dox treatment until either p0 or p21. Delayed H3F3A K27M expression led to an increase in overall survival in both treatment groups across all -cre lines, particularly Olig2-cre (Nestin- p0: 11/11, p21: 14/15, GFAP- p0: 4/4, p21: 9/10, Olig2- p0: 8/8, p21: 7/9), as well as an absence of ataxia and an increase in stature. This suggests that H3F3A K27M expression during a developmental window before p0 is critical to the onset of the observed phenotypes, in addition to the progenitor population being afflicted. Overall these data give insight into the spatial-temporal effects of H3K27M in early tumor development. Citation Format: Evan Lubanszky, Scott Ryall, Robert Siddaway, Byunjin Kim, Taylor Bridge, Sanja Pajovic, Cynthia Hawkins. From map to model: Genetic evolution of diffuse intrinsic pontine glioma provides the framework for accurate tumor modeling [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A35.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.009 | 0.002 |
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".