Abstract 267: MYC maintains the self-renewal of cancer stem cells through the regulation of the glutathione redox system.
Bibliographic record
Abstract
Abstract Cancer stem cells (CSCs) are a rare population of self-renewing cells that can persist even after extensive therapeutic intervention. The molecular mechanism of CSC self-renewal is not yet clear. Here we show that MYC is causally involved in CSC self-renewal through the regulation of glutathione (GSH) redox system. In a MYC-driven conditional transgenic mouse model of T-cell acute lymphoblastic leukemia (T-ALL), we identified Sca-1+ CSCs. We found that these CSCs express the glutathione (GSH) redox system related genes including glutamate cysteine ligase (GCL) and Pyruvate Dehydrogenase Kinase 1 (PDK1) but low levels of expression of the mitochondrial redox enzyme, Superoxide Dismutase 2 (SOD2). Even a brief period of MYC inactivation in the Sca1+ CSCs led to their apoptosis associated with the downregulation of GCL and PDK1, but the upregulation of SOD2, in turn resulting in ROS-generation and mitochondrial damage. Moreover, suppression of SOD2 by siRNA silencing or the use of the peroxide scavenger, ascorbic acid, prevented MYC inactivation from inducing apoptosis in the Sca-1+ CSCs. Finally, in human CSCs, including primary human Chronic Myeloid Leukemia (CML), and human colon cancers, we confirmed that MYC expression was required for high GCL, PDK1 and low SOD2. Even the brief inactivation of MYC in human CSCs resulted in the loss of their self-renewal, as well as the global chance in redox state by decrease in GCL, PDK1 and increase in SOD2. We conclude that high levels of continued MYC expression are essential for CSC self-renewal through regulation of redox state. Citation Format: Bikul Das, Rika Tsuchida, Reza Bayat-Mokhtari, Jason R. Gotlib, Renee Reijo-Pera, Herman Yeger, Felsher W. Dean. MYC maintains the self-renewal of cancer stem cells through the regulation of the glutathione redox system. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 267. doi:10.1158/1538-7445.AM2013-267 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.001 | 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".