Abstract 911: Tyrosine kinase inhibitor Gefitinib selectivley induces apoptosis in Zap70+ chronic lymphocytic leukemia cells and inhibits B cell receptor signaling.
Bibliographic record
Abstract
Abstract Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the western world, is characterized by an accumulation of B cells in the peripheral blood, lymph nodes, and bone marrow leading to immunosuppression. Patients can be stratified into two distinct groups based upon the expression of a T-cell receptor kinase, ZAP70. CLL patients with ≥20% cells staining for the ZAP70 have more aggressive disease and survive shorter times compared with patients with lower ZAP70 expression. Thus, tyrosine kinase inhibitors could be attractive therapeutic agents targeting ZAP70 over expressing CLL cells. In this study, we investigated tyrosine kinase inhibitor gefitinib that has been shown to inhibit tyrosine kinase Syk (a ZAP70 family member) and is not a myelo- or immuno-suppressive drug as other chemotherapeutic agents are in treating CLL. We found using MTT viability assay that the tyrosine kinase inhibitor gefitinib is effective in primary CLL cells with a significant preference for Zap70+ CLL; gefitinib had a median IC50 of 4.5 μM in Zap70+ patient cells and >15.0 μM in Zap70- patient cells. Flow cytometry analysis showed a decrease of viable Zap70+ CLL cells 24 hours post gefitinib treatment. Although gefitinib decreased the viability of the Zap70+ Jurkat T leukemia cell line, it failed to affect T cells from CLL patients. Western blot analysis showed gefitinib inhibited tyrosine phosphorylation of ZAP70 and Syk in CLL cells. In addition, both basal and B cell receptor-stimulated tyrosine phosphorylation was reduced after gefinitib treatment. Compared with other known inhibitors dasatinib and ibrutinib, gefitinib has the same downstream inhibition of Erk and Akt phosphorylation in Zap70+ cells. The significance of Zap70 expression was further determined by treating the Raji B lymphoma cell line transduced with vector control or vector encoding Zap70; indeed Zap70 expression sensitized the B cell line Raji to gefitinib treatment whereas other tyrosine kinase inhibitors were less effective. Therefore, gefitinib inhibits the Zap70 signaling pathway in CLL cells and holds potential as a targeted therapy for aggressive CLL. Citation Format: Rebecca Dielschneider, Wenyan Xiao, Ju Yoon Yoon, Edward Noh, James B. Johnston, Spencer B. Gibson. Tyrosine kinase inhibitor Gefitinib selectivley induces apoptosis in Zap70+ chronic lymphocytic leukemia cells and inhibits B cell receptor signaling. [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 911. doi:10.1158/1538-7445.AM2013-911
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".