This Article Full Text Full Text (PDF) All Versions of this Article: 0008-5472.CAN-08-4252v1 69/13/5424    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Buchner, M. Articles by Zirlik, K. PubMed PubMed Citation Articles by Buchner, M. Articles by Zirlik, K.

Spleen Tyrosine Kinase Is Overexpressed and Represents a Potential Therapeutic Target in Chronic Lymphocytic Leukemia

¹ University Medical Center Freiburg, Department of Hematology and Oncology; ² Institute of Physics, University of Freiburg; and ³ Department of Molecular Immunology, Max-Planck-Institute of Immunobiology, Freiburg, Germany; ⁴ Department of Hematology, Pitie-Salpetriere Hospital, Institut National de la Sante et de la Recherche Medicale U543, UPMC University of Paris VI, Paris, France; and ⁵ Barts and The London School of Medicine, Institute of Cancer, London, United Kingdom

Requests for reprints: Katja Zirlik, Department of Hematology/Oncology, University Medical Center Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany. Phone: 49-761-270-3401; Fax: 49-761-270-7177; E-mail: katja.zirlik{at}uniklinik-freiburg.de.

Key Words: chronic lymphocytic leukemia • B-cell receptor • spleen tyrosine kinase • signal transduction

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, PLC₂, 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. [Cancer Res 2009;69(13):5424–32]

This article has been cited by other articles:

				M. R. McKeller, R. S. Robetorye, P. L. M. Dahia, and R. C. T. Aguiar Integrity of the CBL gene in mature B-cell malignancies Blood, November 5, 2009; 114(19): 4321 - 4322. [Full Text] [PDF]

				M. Butterworth, M. Vogler, M. J. S. Dyer, and G. M. Cohen Response: Microenvironment-dependent resistance to ABT-737 in chronic lymphocytic leukemia Blood, September 17, 2009; 114(12): 2561 - 2562. [Full Text] [PDF]