Abstract A189: 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 rearrangements that result in fusion proteins with aberrant transcriptional regulatory activities. These fusion proteins bind to gene promoters and recruit corepressors such as histone deacetylases (HDACs), which remodel chromatin into a closed conformation thereby silencing genes and contributing to a malignant phenotype. Aberrantly silenced genes include tumor suppressor and pro-differentiation genes. In addition, multiple groups have reported a DNA repair deficient phenotype concurrent with the expression of different fusion proteins in leukemia. Small molecule HDAC inhibitors (HDACi) were devised as a strategy to reverse transcriptional repression. Indeed, many studies have demonstrated the ability of HDACi to re-sensitize leukemic cells to differentiating stimuli. However, other studies have revealed alternate methods by which HDACi exert anti-tumor activity, including induction of apoptosis that may be dependent on induction of ROS, MAPK signaling etc. We find that low doses of HDACi, including Vorinostat and LBH589, induce cell death in the AML cell line U937 in a dose and time-dependant manner. Further, Vorinostat induced cell death in U937 cells is preceded by DNA damage and a G2/M arrest. This correlates with reports that HDACi repress DNA repair, by down-regulating DNA repair genes and by acetylating repair proteins thereby impairing their repair function. Due to the inhibitory effect of leukemic fusion proteins on DNA repair, we predicted that DNA damage induced by HDACi, and thus cell death, would be amplified in AML cells expressing PML-RARα and PLZF-RARα fusion proteins. Sensitivity to Vorinostat and LBH589 was tested in three U937 derived cell lines: PR9 (PML-RARα inducible), B412 (PLZF-RARα inducible) and SN4 (mock transfected control). Indeed, induction of PLZF-RARα increased sensitivity of B412 cells to both Vorinostat- and LBH-mediated cell death. Assaying for DNA damage using alkaline comet assay, PR9 and B412 cells displayed an increase in DNA damage when their respective fusion protein is expressed. Nonetheless, the contribution of DNA damage to HDACi-mediated cell death remains unclear and further study is necessary. These findings are significant as they point to fusion protein expressing AMLs as a target group that may respond better to HDACi-based therapies. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A189.
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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 | 0.001 |
| 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".