Spleen tyrosine kinase is overexpressed and represents a potential therapeutic target in chronic lymphocytic leukemia.
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.
Buchner
Maike
M
University Medical Center Freiburg, Department of Hematology and Oncology, Germany.
Fuchs
Simon
S
Prinz
Gabriele
G
Pfeifer
Dietmar
D
Bartholomé
Kilian
K
Burger
Meike
M
Chevalier
Nina
N
Vallat
Laurent
L
Timmer
Jens
J
Gribben
John G
JG
Jumaa
Hassan
H
Veelken
Hendrik
H
Dierks
Christine
C
Zirlik
Katja
K
D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D001402:B-Lymphocytes / Q000201:enzymology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D003474:Curcumin / Q000627:therapeutic use; D020869:Gene Expression Profiling; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D009367:Neoplasm Staging; D010078:Oxazines / Q000627:therapeutic use; D010766:Phosphorylation; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use; D000072377:Syk Kinase; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
D000970:Antineoplastic Agents; D007135:Immunoglobulin Variable Region; D047908:Intracellular Signaling Peptides and Proteins; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; D010078:Oxazines; D011725:Pyridines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D014740:Vidarabine; D003474:Curcumin; C024352:fludarabine