Epigenetic Regulation of the WNT Canonical Pathway in Mantle Cell Lymphoma.
Bibliographic record
Abstract
Abstract Dysregulation of the WNT signalling pathway is an important event in the pathogenesis of several types of cancer, including colon cancer and acute leukemia. When a WNT protein binds to its receptor, glycogen synthase kinase (GSK)-3β is inactivated by phosphorylation (i.e. pGSK-3β) allowing β-catenin to accumulate in the nucleus and promote transcription of proliferative genes. Conversely, a protein complex that includes GSK-3β initiates destruction of β-catenin if no WNT protein binds its receptor or if an antagonist interferes with WNT ligand-receptor interaction. We previously demonstrated that the WNT canonical pathway is often constitutively active in mantle cell lymphoma (MCL), a subtype of B-cell non-Hodgkin lymphoma. We showed that GSK-3β is phosphorylated, thus inactive, in two-thirds of MCL cases, and that a high level of pGSK-3β correlates with both β-catenin expression and poor patient survival. In order to elucidate the mechanisms of constitutive WNT signalling in MCL, we investigated the RNA expression of six WNT pathway antagonists including WIF-1 using fresh tumour samples and three types of cultured MCL cells. In vivo WIF-1 expression was abundant only in tumours shown to lack pGSK-3β expression. We also examined the regulation of these WNT antagonists by promoter methylation by treating cultured cells with demethylating agent 5-aza-2’-deoxycytidine. The WNT pathway inhibitors were often negatively regulated in MCL-derived cell lines by epigenetic DNA methylation; inhibitors that were not expressed at baseline showed expression after demethylation treatment in at least one MCL cell line. Methylation-specific PCR confirmed that the promoter region of WIF-1 was methylated in almost half of MCL tumour samples. Our data demonstrates that in MCL several antagonists of the canonical WNT pathway are negatively regulated by promoter methylation, thereby allowing aberrant WNT pathway activation. This data confirms that WNT signalling is important in MCL pathogenesis, and identifies potential therapeutic targets for MCL.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".