SYK Inhibition Targets CD38−Mediated Survival and Proliferation Signals in Chronic Lymphocytic Leukemia Cells
| Autor: | Ariane Ott, Natalie Stickel, Marcus Duehren-von Minden, Christine Dierks, Maike Buchner, Hassan Jumaa, Hendrik Veelken, Arlette Dörffel, Katja Zirlik |
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| Rok vydání: | 2011 |
| Předmět: |
Chemokine
medicine.diagnostic_test biology Chronic lymphocytic leukemia Immunology breakpoint cluster region Syk hemic and immune systems Cell Biology Hematology CD38 medicine.disease Biochemistry Hedgehog signaling pathway Flow cytometry Cell biology immune system diseases hemic and lymphatic diseases medicine Cancer research biology.protein Signal transduction |
| Zdroj: | Blood. 118:800-800 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Abstract 800 Chronic Lymphocytic Leukemia (CLL) is characterized by an accumulation of mature monoclonal B cells in the blood, secondary lymphoid tissue, and marrow. The highly variable prognosis of the disease may be predicted using a number of biomarkers, including the expression level of CD38. Human CD38 is a surface glycoprotein with enzymatic activity and the ability to mediate cell-cell interactions by binding the non-substrate ligand CD31. CD31/CD38 interactions drive CLL proliferation and chemotaxis, and increase CXCL-12-mediated signals and homing of CLL cells towards lymphoid organs. We and others have previously identified SYK, a key component of the BCR signalling pathway, as a candidate for targeted therapy in CLL due to its enhanced expression and activity and the apoptotic effects of pharmacological SYK inhibition even in the context of the microenvironment. In this study, we demonstrate direct involvement of SYK in the CD38 signaling pathway and that SYK inhibition may prevent CD38−mediated CLL cell proliferation and migration. CD38 stimulation of primary CLL cells by its ligand CD31 resulted in SYK activation as indicated by phospho-protein analysis by flow cytometry (n=18, p=0.0002) and immunoblotting. Analysis of CD38 expression on CLL cells by flow cytometry with SYK inhibition using the pharmacological SYK inhibitor R406 (Sellek) revealed a significant decrease of CD38 by 31% (n=25, p Taken together, our data demonstrate direct involvement of SYK in the CD38 signaling pathway. Beyond the known effects of SYK inhibition on chemokine- and integrin mediated CLL-stroma interactions, these data establish interference with the CD31/CD38 axis as novel therapeutic mode of action of SYK inhibition in CLL. Since CD38 expression identifies CLL cells with high proliferative and migratory function and clinically associates with poor responsiveness to chemotherapy SYK inhibition may be a particularly promising therapeutic option in CLL patients expressing CD38. Disclosures: No relevant conflicts of interest to declare. |
| Databáze: | OpenAIRE |
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