LMP1 and Dynamic Progressive Telomere Dysfunction: A Major Culprit in EBV-Associated Hodgkin’s Lymphoma
Bibliographic record
Abstract
Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is expressed in germinal-center-derived, mononuclear Hodgkin (H) and multinuclear, diagnostic Reed-Sternberg (RS) cells in classical EBV-positive Hodgkin's lymphoma (cHL). LMP1 expression in EBV-negative H-cell lines results in a significantly increased number of RS cells. In a conditional, germinal-center-derived B-cell in vitro system, LMP1 reversibly down-regulates the shelterin proteins, telomeric repeat binding factor (TRF)1, TRF2, and protection of telomeres (POT)1. This down-regulation is associated with progressive 3D shelterin disruption, resulting in telomere dysfunction, progression of complex chromosomal rearrangements, and multinuclearity. TRF2 appears to be the key player. Thus, we hypothesize that the 3D interaction of telomeres and TRF2 is disrupted in H cells, and directly associated with the formation of H and RS cells. Using quantitative 3D co-immuno-TRF2-telomere fluorescent in situ hybridization (3D TRF2/Telo-Q-FISH) applied to monolayers of primary H and RS cells, we demonstrate TRF2-telomere dysfunction in EBV-positive cHL. However, in EBV-negative cHL a second molecular mechanism characterized by massive up-regulation of TRF2, but attrition of telomere signals, is also identified. These facts point towards a shelterin-related pathogenesis of cHL, where two molecularly disparate mechanisms converge at the level of 3D Telomere-TRF2 interactions, leading to the formation of RS cells.
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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".