|Publication Type||Journal Article|
|Year of Publication||2008|
|Authors||Chen, L, Monti, S, Juszczynski, P, Daley, J, Chen, W, Witzig, TE, Habermann, TM, Kutok, JL, Shipp, MA|
|Pages||2230 - 7|
|Keywords||Antig, Apoptosis, Cancer, Cell Culture Techniques, Cell Division, Cell Line, Diffuse, Enzyme Inhibitors, Flow Cytometry, Humans, Intracellular Signaling Peptides and Proteins, Large B-Cell, Lymphoma, Oxazines, Protein-Tyrosine Kinases, Pyridines, Receptors, Tumor|
The role of B-cell receptor (BCR)-mediated survival signals in diffuse large B-cell lymphoma (DLBCL) remains undefined. Ligand-induced BCR signaling induces receptor oligomerization, Igalpha/beta immunoreceptor tyrosine-based activation motif (ITAM) phosphorylation, and activation of the spleen tyrosine kinase (SYK), which initiates downstream events and amplifies the initial BCR signal. BCRs also transmit low-level tonic survival signals in the absence of receptor engagement. Herein, we assess the role of SYK-dependent tonic BCR survival signals in DLBCL cell lines and primary tumors and evaluate the efficacy of an ATP-competitive inhibitor of SYK, R406, in vitro. R406 induced apoptosis of the majority of examined DLBCL cell lines. In R406-sensitive DLBCL cell lines, R406 specifically inhibited both tonic- and ligand-induced BCR signaling (autophosphorylation of SYK525/526 and SYK-dependent phosphorylation of the B-cell linker protein [BLNK]). The majority of examined primary DLBCLs also exhibited tonic- and ligand-induced BCR signaling; in these primary tumors, BCR signaling was also inhibited by R406. Of note, BCR-dependent and R406-sensitive DLBCL cell lines were independently identified as "BCR-type" tumors by transcriptional profiling. Therefore, SYK-dependent tonic BCR signaling is an important and potentially targetable survival pathway in some, but not all, DLBCLs. In addition, R406-sensitive DLBCLs can be identified by their transcriptional profiles.