| Title | Spleen tyrosine kinase is overexpressed and represents a potential therapeutic target in chronic lymphocytic leukemia. | | Author(s) | Buchner M, Fuchs S, Prinz G, Pfeifer D, Bartholomé K, Burger M, Chevalier N, Vallat L, Timmer J, Gribben JG, Jumaa H, Veelken H, Dierks C, Zirlik K | | Institution | University Medical Center Freiburg, Department of Hematology and Oncology, Germany. | | Source | Cancer Res 2009 Jul 1; 69(13):5424-32. | | MeSH | Antineoplastic Agents
Antineoplastic Combined Chemotherapy Protocols
Apoptosis
B-Lymphocytes
Caspase 3
Cell Line, Tumor
Curcumin
Gene Expression Profiling
Humans
Immunoglobulin Variable Region
Intracellular Signaling Peptides and Proteins
Leukemia, Lymphocytic, Chronic, B-Cell
Mutation
Neoplasm Staging
Oxazines
Phosphorylation
Prognosis
Protein-Tyrosine Kinases
Proto-Oncogene Proteins c-akt
Pyridines
Vidarabine
| | Abstract | B-cell receptor signaling contributes to apoptosis resistance in chronic lymphocytic leukemia (CLL), limiting the efficacy of current therapeutic approaches. In this study, we investigated the expression of spleen tyrosine kinase (SYK), a key component of the B-cell receptor signaling pathway, in CLL and its role in apoptosis. Gene expression profiling identified enhanced expression of SYK and downstream pathways in CLL compared with healthy B cells. Immunoblotting showed increased expression and phosphorylation of SYK, PLCgamma(2), signal transducers and activators of transcription 3, and extracellular signal regulated kinase 1/2 in CLL compared with healthy B cells, suggesting enhanced activation of these mediators in CLL. SYK inhibitors reduced phosphorylation of SYK downstream targets and induced apoptosis in primary CLL cells. With respect to prognostic factors, SYK inhibitors exerted stronger cytotoxic effects in unmutated and ZAP70(+) cases. Cytotoxic effects of SYK inhibitors also associated with SYK protein expression, potentially predicting response to therapy. Combination of fludarabine with SYK Inhibitor II or R406 increased cytotoxicity compared with fludarabine therapy alone. We observed no stroma-contact-mediated drug resistance for SYK inhibitors as described for fludarabine treatment. CD40 ligation further enhanced efficacy of SYK inhibition. Our data provide mechanistic insight into the recently observed therapeutic effects of the SYK inhibitor R406 in CLL. Combination of SYK inhibitors with fludarabine might be a novel treatment option particularly for CLL patients with poor prognosis and should be further evaluated in clinical trials. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, Non-U.S. Gov't
| | PubMed ID | 19549911 |
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