STEM-28. DOT1L EPIGENETICALLY REGULATES GBM BRAIN TUMOR STEM CELLS
Bibliographic record
Abstract
The median survival for patients diagnosed with Glioblastoma (GBM) is only 14 months, due to recurrence, despite current treatment options of surgery, radio- and chemo- therapies. Recurrence results from the invasion of GBM cancer cells away from the initial cancerous mass and may be due to brain tumor stem cells (BTSCs) that are resistant to therapy and capable of tumor initiation. Recently, epigenetic-based therapies have become of great interest given that, unlike genomic mutations, epigenetic alterations are potentially reversible. Disrupter of telomeric silencing-1-like (DOT1L) is the only known histone methyltransferase responsible for histone-3-lysine-79 methylation (H3K79me), an epigenetic mark associated with active gene transcription. Previous studies investigating the therapeutic implications of targeting DOT1L in cancer have shown that its inhibition in leukemia results in cancer cell death and, in solid cancers, decreases metastasis. We investigated the role of DOT1L in GBM BTSCs. Long term treatment with the DOT1L inhibitor EPZ-5676 decreased H3K79me2 levels in BTSCs and altered BTSC sphere morphology, sphere initiating frequency, proliferation, migration and invasion. To investigate the mechanism by which DOT1L may regulate GBM tumorigenesis and growth we performed qPCR, flow cytometry, RNA-sequencing and H3K79me2 ChIP-sequencing of BTSC lines, following treatment with EPZ-5676. We found that DOT1L inhibition decreases the expression of GBM stem and progenitor cell genes and increases the expression of genes associated with neuronal and astrocytic differentiation. Furthermore, H3K79me2 ChIP sequencing revealed that DOT1L histone methylation was reduced within the gene body of stem and progenitor cell genes. Flank xenograft studies, of mice treated with EPZ-5676, revealed that DOT1L inhibition promotes neuronal and astrocytic differentiation in tumors. Ongoing pre-clinical studies are assessing the effect of DOT1L inhibition on survival in an orthotopic xenograft model of GBM and investigating rational combinatorial targeting strategies, with a long-term aim of preventing GBM recurrence and improving overall patient survival.
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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".