MEDU-13. CONVERGENCE OF BMI1 AND CHD7 ON ERK SIGNALLING IN MEDULLOBLASTOMA
Bibliographic record
Abstract
Medulloblastoma is the most common malignant paediatric brain tumour and is associated with high morbidity and mortality. Medulloblastomas are currently classified into four distinct molecular subgroups (WNT, SHH, Group 3 and Group 4) with different prognosis and responses to therapy. The Polycomb group protein BMI1 sustains self-renewal of neural stem cells and promotes proliferation of neural progenitors during development and in adult tissue homeostasis. Upregulation of BMI1 has been described in a plethora of cancers, including medulloblastoma, and it correlates with clinical stage and poor prognosis. BMI1 is overexpressed across all medulloblastoma subgroups but it is highest in Group 4 where it sustains tumour growth. Insertional mutagenesis of the T2Onc2 transposon by Sleeping Beauty transposase in glutamatergic progenitors overexpressing BMI1 leads to medulloblastoma formation, while neither Bmi1 over-expression nor T2Onc2 transposition alone drives tumorigenesis. These medulloblastomas show frequent inactivating insertions in the chromatin remodelling factor Chd7 (Chromodomain helicase DNA binding factor 7), suggesting that upregulation of BMI1 together with CHD7 loss of function can cooperate to initiate MB tumorigenesis. A BMI1High;CHD7Low molecular signature is associated with poor prognosis in human medulloblastoma and single copy loss and inactivating mutations of CHD7 are found in medulloblastoma Group 4. Silencing of CHD7 in primary patient-derived Group 4 medulloblastoma cells results in increased proliferation and upregulation of markers characteristic of undifferentiated and highly proliferative progenitors. Notably, we demonstrate that the proliferative phenotype driven by CHD7 knockdown is dependent on BMI1. Finally we show a molecular convergence on ERK signalling mediated by CHD7 and dependent on BMI1 expression. These results shed further light on 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 | 0.000 |
| 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".