Abstract 4322: Atrx inactivation drives motility and dysregulates differentiation in glioma cells of origin through global epigenomic remodeling
Bibliographic record
Abstract
Abstract Comprehensive genomic profiling in cancer continues to reveal frequent alterations in epigenetic regulators, firmly implicating chromatin biology in the oncogenic process. For instance, genetic inactivation of the SWI/SNF chromatin regulator ATRX (α-thalassemia mental retardation X-linked) represents a defining molecular alteration in both adult and pediatric malignant glioma, and occurs frequently in other cancers as well. ATRX deficiency has been linked to a wide spectrum of physiological dysfunction, including aberrant gene regulation, abnormal telomere maintenance, genomic instability, and aneuploidy. However, the precise oncogenic mechanism(s) induced by ATRX deficiency remain unclear, particularly those involving epigenomic dysregulation. To model these events in putative glioma cells of origin, we inactivated Atrx in primary murine neuroepithelial progenitors (mNPCs). Atrx loss, especially when coupled with Tp53 inactivation, promoted mNPC motility while also modulating differentiation state and potential, effectively recapitulating characteristic disease phenotypes and molecular features. Moreover, these phenotypes correlated with altered gene expression profiles in functionally relevant molecular networks (e.g. cell differentiation and migration). Integrating these transcriptional changes with shifts in chromatin accessibility occurring with Atrx deficiency, along with genome-wide Atrx distribution as determined by ChIP-seq, revealed highly significant spatial correlations between differentially expressed genes, regions of altered chromatin compaction, and genomic sites normally occupied by Atrx. Finally, target genes mediating specific Atrx-deficient phenotypes in vitro exhibited similarly selective misexpression in ATRX-mutant human glioma tissues and cell lines. These findings demonstrate that, in appropriate cellular and molecular contexts, ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes. Citation Format: Carla Danussi, Promita Bose, Pedro Silberman, John S. Van Arnam, Mark Vitucci, Oliver Tang, Adriana Heguy, Timothy A. Chan, Erik P. Sulman, Frederick Lang, Chad J. Creighton, Benjamin Deneen, C Ryan Miller, David J. Picketts, Kasthuri Kannan, Jason T. Huse. Atrx inactivation drives motility and dysregulates differentiation in glioma cells of origin through global epigenomic remodeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4322.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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".