BCR-ABL Induces Autocrine IGF-1 Signaling.
Bibliographic record
Abstract
Abstract BCR-ABL is responsible for the initial phase of chronic myelogenous leukemia (CML), which is effectively treated by the BCR-ABL tyrosine kinase inhibitor imatinib. Over time, patients become resistant to treatment and progress to blast crisis, an event that is driven by additional genetic and epigenetic aberrations. Recently, we showed that RIZ1 expression decreases in blast crisis and that re-expression of RIZ1 inhibits IGF-1 expression. IGF-1 signaling is required in many stages of hematopoiesis and inappropriate activation of autocrine IGF-1 signaling may facilitate transformation to blast crisis. In this study, we examined mechanisms used by CML blast crisis cells to activate IGF-1 expression. We monitored the effects of small molecule inhibitors and shRNAs of BCR-ABL, HCK, and STAT5b on IGF-1 expression, proliferation, and apoptosis in CML blast crisis cell lines. We used chromatin immunoprecipitation assays to confirm that STAT5b associates with the IGF-1 promoter in a BCR-ABL-dependent manner. We found that BCR-ABL activates autocrine IGF-1 signaling using HCK and STAT5b. Imatinib blocks HCK phosphorylation, STAT5b phosphorylation, and the association of STAT5b with the IGF-1 promoter. Inhibition of these signaling components using small molecule drugs or shRNA inhibits IGF-1 expression, decreases proliferation, and enhances apoptosis. The effects of imatinib are partially reversed by the addition of exogenous IGF-1. Furthermore, treatment of CML blast crisis cell lines with the IGF-1 receptor inhibitor AG1024 decreases proliferation and enhances apoptosis and this activity correlates with IGF-1 expression levels. Our study highlights autocrine IGF-1 signaling as an important event in the transformation to blast crisis and provides a novel mechanism to explain the activity of IGF-1R and HCK inhibitors in blocking blast crisis phenotypes. Together, our results provide further support for the therapeutic potential of IGF-1 signaling components in treating CML, especially in cases associated with elevated autocrine IGF-1 expression.
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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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".