Abstract A35: From map to model: Genetic evolution of diffuse intrinsic pontine glioma provides the framework for accurate tumor modeling
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,009 | 0,002 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».