Dual action of pimozide through lysosome disruption and inhibition of STATs induces apoptosis in chronic lymphocytic leukemia (CLL)
Bibliographic record
Abstract
ABSTRACT: Chronic lymphocytic leukemia (CLL) progression and therapeutic resistance are driven in large part by protective signals from the tumor microenvironment (TME), which includes T-cell-derived cytokines such as interleukin-4 (IL-4) that promote survival via signal transducer and activator of transcription (STAT) signaling and upregulation of antiapoptotic proteins such as the B-cell lymphoma 2 (BCL-2) family member myeloid cell leukemia 1 (MCL-1). Although the BCL-2 inhibitor venetoclax has demonstrated significant clinical efficacy, microenvironment-induced resistance, particularly by MCL-1 upregulation, remains a major limitation. Here, we identify the US Food and Drug Administration-approved antipsychotic drug pimozide as a dual-function agent that induces lysosome membrane permeabilization, leading to apoptosis in CLL cells through increased reactive oxygen species production. In addition, pimozide inhibited STAT5 phosphorylation, reduced IL-4-induced MCL-1 expression, and prevented IL-4/CD40L-mediated inhibition of apoptosis. Importantly, pimozide remains effective in inducing apoptosis in CLL cells from patients who have relapsed after therapy. Pimozide also synergizes with venetoclax to induce apoptosis in CLL cells even after IL-4/CD40L signaling. This suggests that dual targeting of lysosomal function and STAT signaling represents a promising therapeutic approach to improve venetoclax efficacy and overcome TME-mediated drug resistance in CLL.
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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 | 0.000 | 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 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".