Targeting EZH2-mediated methylation of histone 3 inhibits proliferation of pediatric acute monocytic leukemia cells <i>in vitro</i>
Bibliographic record
Abstract
Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and a catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the mono-, di-, and tri-methylation of histone H3 at Lys 27 (H3K27me3) to facilitate chromatin-remodeling and gene-silencing functions. Previous reports showed a significant association of EZH2 aberrations in pediatric cancers, such as soft tissue sarcomas and glioblastoma. Recent reports in human subjects and animal models have also suggested a central role of EZH2 in the induction and progression of acute myeloid leukemia. In this study, we aimed to investigate the molecular status of EZH in cell lines derived from distinct pediatric leukemia to assess the efficacy of targeting EZH2 to suppress cancer cell survival and proliferation. Our results showed that EZH2 protein is overexpressed in the pediatric monocytic cell-line THP-1, but not in other leukemia-derived cell lines MV4;11 and SEM. Screening a panel of methyltransferase inhibitors revealed that three inhibitors; GSK126, UNC1999 and EPZ-5687 are the most potent inhibitors that suppressed EZH2 activity selectively on lysine 27 which resulted in increased apoptosis and inhibition of AKT and ERK protein phosphorylation in THP-1 cells. Our data demonstrated a significant increase in apoptosis in cells treated with drug combination (EZH2i and selinexor) compared to EZH2i inhibitors alone. Taken together, our data provide initial evidence that targeting EZH2 is a promising therapeutic strategy for the treatment of subtypes of pediatric AML. Also, combining EZH2 inhibitors with selinexor may increase the treatment efficacy in these patients.
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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) | 0.001 | 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".