Identification of SCL and LMO Oncogenes as Transcriptional Repressors of HEB/E2A in the Thymus through Functional Genomic/Genetic Approaches.
Bibliographic record
Abstract
Abstract The SCL and LMO oncogenes are frequently activated in childhood T cell acute leukemia (T-ALL). SCL is a bHLH transcription factor that forms heterodimers with other members, specifically HEB and E2A. SCL can either activate or repress transcription but its mechanism of action as an oncogene remains to be clarified. Ectopic expression of SCL and LMO in transgenic mice causes thymocyte differentiation arrest during the preleukemic phase with aberrant differentiation at the DN3–DN4 stage, prior to the acquisition of CD4 and CD8. We therefore took several approaches to define the mechanism underlying this differentiation arrest. Using a CD3e-deficient background to eliminate preTCR signaling effects, an event that is not essential for leukemogenesis, we first analyzed global gene expression of pre-leukemic SCLtg/LMOtg DN3 thymocytes against their non-transgenic littermates via the Affymetrix platform. In this context, SCL/LMO globally affects the expression of both positive and negative targets of E2A/HEB. These results were confirmed by real-time quantitative PCR, showing that SCL/LMO repress E2A/HEB activity. Second, bioinformatic analysis of genes significantly affected by SCL/LMO allowed us to identify phylogenetically conserved HEB/E2A binding sites within the promoter regions of half of these genes. E2A/HEB binding was directly assessed through chromatin immunoprecipitation of primary thymocytes, confirming known target genes and revealing novel ones. This assay also showed that SCL associates with HEB and/or E2A on DNA. Moreover, structure function analysis indicate that transcription inhibition by SCL depends on its HLH domain but not on LMO interaction. We therefore conclude that SCL inhibits thymocyte differentiation by inhibiting E2A/HEB targets that include genes required for thymocyte differentiation, cell signalling, DNA repair and replication. Finally, using a genetic approach we show that SCL/LMO collaborates with HEB haploinsufficiency in inducing leukemia. Our observations therefore reveal that the repression of HEB/E2A by SCL/LMO is a crucial step in T cell transformation. Support from CIHR and FRSQ.
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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 | 0.001 | 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) | 0.002 | 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".