c-MYC Is a Major Downstream Target of NOTCH in T-Cell Acute Lymphoblastic Leukemia.
Bibliographic record
Abstract
Abstract We recently reported that activating mutations in the NOTCH1 receptor occur in a high percentage of primary human T-cell acute lymphoblastic leukemias (T-ALL). Withdrawal of NOTCH signals by treatment with γ-secretase inhibitors (GSI) or by transduction with a dominant-negative Mastermind-like-1 polypeptide (a specific NOTCH pathway inhibitor) induces growth arrest of many T-ALL cell lines, suggesting that NOTCH supplies signals that are needed for maintenance of growth of T-ALL cells. In order to identify downstream targets of NOTCH that mediate these effects, we performed gene expression profiling on NOTCH signaling-dependent T-ALL cell lines before and after NOTCH inhibition. Among a number of identified candidate genes was c-MYC, which was of particular interest given its importance in promoting cellular growth and its known dysregulation in a number of hematolymphoid neoplasms. c-MYC was down-regulated following NOTCH inhibition, and rapidly up-regulated following release of NOTCH inhibition, even in the presence of protein synthesis inhibitors, suggesting that it is a direct NOTCH transcriptional target. Further, a subset of murine and human T-ALL cell lines were rescued from GSI-mediated growth arrest by c-MYC-expressing retroviruses. The failure of c-MYC to rescue some NOTCH-dependent cell lines likely stems from differences in cellular context, such as collaborating oncogenic lesions and/or the stage of T cell development the cell lines recapitulate. Nevertheless, these data implicate c-MYC as a major downstream target of NOTCH in T-ALL.
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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".