TMOD-17. CONVERGENCE OF BMI1 AND CHD7 ON ERK SIGNALLING IN MEDULLOBLASTOMA
Bibliographic record
Abstract
Medulloblastoma is the most common malignant brain tumour of childhood, and a common cause of pediatric morbidity and mortality. Medulloblastomas have been dissected into four distinct molecular subgroups (WNT, SHH, Group 3, Group 4) with divergent clinical and biological profiles. The Polycomb group protein Bmi1 is upregulated in a variety of cancers, has a positive correlation with clinical grade/stage and poor prognosis and it is a highly druggable molecule. Bmi1 is overexpressed across all MB subgroups; the growth of SHH and Group 4 MB is dependent on Bmi1 expression. Genome wide in vivo insertional mutagenesis (T2Onc2) driven by the Sleeping Beauty (SB11) transposase in glutamatergic progenitor cells engineered to over-express Bmi1 results in medulloblastoma formation, while neither Bmi1 over-expression nor T2Onc2 transposition alone drives tumorigenesis. On the Bmi1 over-expressing background, we observe frequent T2Onc2 inactivating insertions in the chromatin remodelling factor Chd7 (Chromodomain helicase DNA binding factor 7), suggesting that Bmi1 overexpression and Chd7 loss of function cooperate to induce medulloblastoma. High expression of BMI1 in combination with low expression of CHD7 is associated with a poor prognosis in human medulloblastoma. Loss of function mutations of CHD7are observed in medulloblastoma, particularly in Group 4. CHD7 knockdown in patient-derived Group 4 medulloblastoma cells led to increased proliferation and increased expression of markers of undifferentiated and highly proliferative progenitor cells both in vitro and in xenografts. Importantly, we show the BMI1-dependency of the phenotype observed upon CHD7 knockdown and the molecular convergence on ERK signalling. These finding extend the current knowledge of the role of BMI1 and CHD7 in medulloblastoma pathogenesis and raise the possibility that pharmacological targeting of BMI1 or ERK may be particularly indicated in a subgroup of medulloblastoma with low expression level of CHD7.
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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) | 0.004 | 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".