RBL2 Regulates Cardiac Sensitivity to Anthracycline Chemotherapy
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Bibliographic record
Abstract
Anthracycline chemotherapies cause heart failure in a subset of cancer patients. We previously reported that the anthracycline doxorubicin (DOX) induces cardiotoxicity through the activation of cyclin-dependent kinase 2 (CDK2). The aim of this study was to determine whether retinoblastoma-like 2 (RBL2/p130), an emerging CDK2 inhibitor, regulates anthracycline sensitivity in the heart. Rbl2−/− mice and Rbl2+/+ littermates received DOX (5 mg/kg/wk for 4 weeks intraperitoneally, 20 mg/kg cumulative). Heart function was monitored with echocardiography. The association of RBL2 genetic variants with anthracycline cardiomyopathy was evaluated in the SJLIFE (St. Jude Lifetime Cohort Study) and CPNDS (Canadian Pharmacogenomics Network for Drug Safety) studies. The loss of endogenous Rbl2 increased basal CDK2 activity in the mouse heart. Mice lacking Rbl2 were more sensitive to DOX-induced cardiotoxicity, as evidenced by rapid deterioration of heart function and loss of heart mass. The disruption of Rbl2 exacerbated DOX-induced mitochondrial damage and cardiomyocyte apoptosis. Mechanistically, Rbl2 deficiency enhanced CDK2-dependent activation of forkhead box O1 (FOXO1), leading to up-regulation of the proapoptotic protein Bim. The inhibition of CDK2 desensitized Rbl2-depleted cardiomyocytes to DOX. In wild-type cardiomyocytes, DOX exposure induced Rbl2 expression in a FOXO1-dependent manner. Importantly, the rs17800727 G allele of the human RBL2 gene was associated with reduced anthracycline cardiotoxicity in childhood cancer survivors. Rbl2 is an endogenous CDK2 inhibitor in the heart and represses FOXO1-mediated proapoptotic gene expression. The loss of Rbl2 increases sensitivity to DOX-induced cardiotoxicity. Our findings suggest that RBL2 could be used as a biomarker to predict the risk of cardiotoxicity before the initiation of anthracycline-based chemotherapy.
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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 | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.003 |
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 it