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

被引：151

作者：

Buchner, Maike ^{[1
]}

Fuchs, Simon ^{[1
]}

Prinz, Gabriele ^{[1
]}

Pfeifer, Dietmar ^{[1
]}

Bartholome, Kilian ^{[3
]}

Burger, Meike ^{[1
]}

Chevalier, Nina ^{[1
]}

Vallat, Laurent ^{[4
]}

Timmer, Jens ^{[3
]}

Gribben, John G. ^{[5
]}

Jumaa, Hassan ^{[2
]}

Veelken, Hendrik ^{[1
]}

Dierks, Christine ^{[1
]}

Zirlik, Katja ^{[1
]}

机构：

[1] Univ Med Ctr Freiburg, Dept Hematol & Oncol, D-79106 Freiburg, Germany

[2] Max Planck Inst Immunobiol, Dept Mol Immunol, D-7800 Freiburg, Germany

[3] Univ Freiburg, Inst Phys, Freiburg, Germany

[4] Univ Paris 06, Dept Hematol, Pitie Salpetriere Hosp, Inst Natl Sante & Rech Med,U543, Paris, France

[5] Barts & London Queen Marys Sch Med & Dent, Inst Canc, London, England

来源：

CANCER RESEARCH | 2009年 / 69卷 / 13期

关键词：

B-CELL RECEPTOR; GENE MUTATION STATUS; ANTIGEN RECEPTOR; CD38; EXPRESSION; SYK; APOPTOSIS; LYMPHOMA; ACTIVATION; ZAP-70; CLL;

D O I：

10.1158/0008-5472.CAN-08-4252

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 tryrosine 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, PLC gamma 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. [Cancer Res 2009;69(13):5424-32]

引用

页码：5424 / 5432

页数：9