A novel regulatory circuit of ATG4B and SESN3 promotes T cell leukemogenesis
Bibliographic record
Abstract
BACKGROUND: T cell acute lymphoblastic leukemia is a fatal hematological malignancy. Despite the treatment progress, no targeted therapy is available currently, which urges to deepen the understanding of the underlying mechanism of T-ALL cell growth/survival. Autophagy is a conserved cellular process, which plays a dual role in human cancers. Nevertheless, many aspects of the involvement of autophagy in T-ALL are not fully understood. METHODS: T-ALL patient cells and normal control cells were subjected to RT‒qPCR analysis. Gene silence and overexpression was used to study the function of ATG4B and sestrin 3 (SESN3) in T-ALL cells. Atg4b deficient mice were used to study the role of Atg4b in normal hematopoietic cells and T cell development. The efficacy of S130, an ATG4B inhibitor to suppress T-ALL cell growth was evaluated in xenograft models. RESULTS: The results showed that the expression of several autophagy-related genes (especially ATG4B) was significantly higher in T-ALL patient cells than control cells. ATG4B ablation decreased autophagic flux and inhibited T-ALL cell growth. In contrast, Atg4b depletion had mild effects on normal hematopoiesis and T cell development. RNA-seq data and subsequent studies revealed a novel regulatory circuit of ATG4B and SESN3, and the results indicated that SESN3 hampered T-ALL cell growth via the inhibition of both mTOR/S6K/protein synthesis pathway and autophagy. Importantly, S130 exhibited anti-leukemia activity in xenograft models. CONCLUSIONS: The present study demonstrates that a novel ATG4B-SESN3 regulatory circuit plays a crucial role in T cell leukemogenesis, which suggests that targeting ATG4B is a promising strategy for T-ALL treatment.
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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 | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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".