Inhibition of telomerase and ALT pathways in MDS/AML cell lines
Bibliographic record
Abstract
Abstract Background: The ability of human cancer cells to maintain telomere length over successive cell divisions rapidly emerged as an adaptive mechanism acquired by cancer cells to defy cell senescence and mortality. This mechanism of immortality of cancerous cells was first demonstrated in the 1990s. Telomerase activation is the most common pathway to avoid telomere length erosion and is used by 85% of all tumor cells, while alternative lengthening of telomere ALT is used by the remainder. Some tumors, albeit rare, demonstrate the co-activation of both telomere maintenance pathways. The consequence of continued cell proliferation of tumor cells despite their critically short telomeres allows for ongoing genomic instability and its propagation to the next generation of cells. We hypothesized that a consecutive inhibition of the two telomere maintenance pathways by first inhibiting telomerase followed by the ALT pathway inhibition will kill cancer cells. Methods: We performed successive inhibition of telomerase over time (0h-144h) followed by ALT pathway (72h-144h) on MDS-92, MDS-L (Myelodysplastic Syndromes), and OCI-AML3 (Acute Myeloid Leukemia) cell lines, and used Normal Human Primary Fibroblasts (GL51/92 Roe) as controls. Cell death was assayed by live cell imaging using NucGreen™ Dead 488 and trypan blue exclusion. Results: Consecutive inhibition of both telomere maintenance pathways showed a significant decrease in cell viability rate over 72h of treatment with 200 µM SB1532 that were 25% for MDS-L and 27% for MDS92 and 38% for OCI-AML3. Cell death was increased by adding 4 nM Trabectedin (ALT inhibition) for an additional 3 days, leading to the viability rate results at 144 hours that were 1% for MDS-L, 0% for MDS92, and 9% for OCI-AML3. Meanwhile, primary fibroblast cells at low and high passages did not show sensitivity to these molecules with a cell viability rate of 93% and 87% after 144 hours, respectively. Conclusion: Inhibition of both telomere maintenance pathways in MDS/AML cell lines demonstrated a decrease in cell viability and increased cell death while primary fibroblasts showed no significant effect on survival. In future, study of primary cells from patients is necessary to confirm these results and to pave the way for cancer treatment in hematological and solid tumor neoplasias with molecules and/or small molecules targeting telomerase and ALT pathways.
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 | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".