Abstract 2136: Expression of fusion proteins in acute myeloid leukemia cells increases sensitivity to histone deacetylase inhibitors
Bibliographic record
Abstract
Abstract Acute myeloid leukemias (AMLs) are often characterized by chromosomal translocations resulting in the expression of fusion proteins (FP). Some FP have been demonstrated to recruit histone deacetylases (HDACs) and repress the expression of DNA repair genes. This may result in an increased sensitivity to histone deacetylase inhibitors (HDI) due to their ability to also down-regulate DNA repair gene expression and induce DNA damage. We have tested the sensitivity of PLZF-RARα, PML-RARα and AML1-ETO inducible cell lines to HDI in order to characterize changes in the mechanisms of cell death. Treatment of U937 cells with vorinostat results in DNA damage as measured by the COMET assay, followed by cell death. To test the effect of FP expression, U937 cells stably transfected with PLZF-RARα, PML-RARα or AML1-ETO cDNA under the control of a tetracycline-off or a zinc-inducible system were treated with vorinostat and assayed for cell death in the presence/absence of FP. FP expression resulted in increased cell death and caspase-3/7 activation. This effect was found to be largely caspase driven as pre-treatment with the pan-caspase inhibitor Z-VAD-FMK resulted in protection against vorinostat-induced cell death. In addition, FP expressing cells were also exposed to the DNA-targeting agents Doxorubicin, Etoposide, Cisplatin and ionizing radiation. Again, FP expression resulted in increased cell death. In addition, we investigated the effect of FP expression on vorinostat sensitivity using a PLZF-RARα murine hematopoietic model. A retroviral expression system was used to overexpress PLZF-RARα in lineage-depleted (Lin-) murine hematopoietic progenitors, followed by vorinostat treatment in the absence/presence of PLZF-RARα. The increased sensitivity of FP expressing cells to HDI and DNA-targeting agents suggests a mechanism where the combination of an FP expression and HDI results in an increased accumulation of DNA damage, leading to enhanced cell death. These findings are significant as they point to FP expressing AMLs as a target group that may respond better to HDI-based therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2136. doi:10.1158/1538-7445.AM2011-2136
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) | 0.003 | 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".