What doesn’t kill you makes you stronger – <i>bcl-2</i> promotes survival independent of proliferation
Bibliographic record
Abstract
Combination therapy with the BCL-2 inhibitor, venetoclax, and hypomethylating agents produces high response rates in elderly patients with acute myeloid leukemia unfit for induction chemotherapy, setting a new standard of care for these patients. 1These clinical results build on decades of fundamental, translational, and clinical research into BCL-2 and apoptosis.The bcl-2 gene (now known as BCL2) was originally discovered in 1984 by Yoshihide Tsujimoto in Croce's laboratory; he identified it as the fusion partner with the immunoglobulin heavy chain locus in patients with B-cell malignancies and the t(14;18) translocation. 2 Subsequently, Reed et al. reported that bcl-2 was an oncogene, the first oncogene identified without a viral counterpart.However, the biological function and mechanism by which bcl-2 promoted malignancy remained unknown.In a landmark paper published in 1988, Drs. Vaux, Cory and Adams described the first cellular mechanism of action of bcl-2. 3In their letter to Nature, a paper with three figures and neither supplementary material nor volumes of extended data, they showed that overexpression of bcl-2 prevented cell death.Interleukin (IL)-3-dependent FDC-P1 myeloid cells were transduced with human bcl-2 cDNA and then IL-3 was withdrawn.All control and c-myc-transduced FDC-P1 cells died 4 days after IL-3 withdrawal.In contrast, 60% of the cells overexpressing bcl-2 remained viable.Although viable, cells overexpressing bcl-2 did not proliferate and did not become tumorigenic when injected into mice.The authors concluded that bcl-2 functions as an oncogene by promoting prolonged cell survival, independent of its effects on cell proliferation.Subsequently, bcl-2 was shown to protect cells from a specific mechanism of cell death, called apoptosis.Over the following years and decades, a clearer picture of the mechanisms of action of bcl-2 emerged.A family of pro-and anti-apoptotic proteins structurally related to BCL-2 were identified.BCL-2 and its family members were localized to the mitochondrial outer membrane where they regulated mitochondrial membrane potential.Inhibiting BCL-2 led to a collapse of mitochondrial membrane potential and release of mitochondrial proteins, including cytochrome c, which triggered apopto-
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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 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
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".