Scientific Publications

SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma

Publication TypeJournal Article
AuthorsChen, Linfeng, Monti Stefano, Juszczynski Przemyslaw, Daley John, Chen Wen, Witzig Thomas E., Habermann Thomas M., Kutok Jeffery L., and Shipp Margaret A.
AbstractThe 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.
Year of Publication2008
JournalBlood
Volume111
Issue4
Pages2230 - 7
Date Published (YYYY/MM/DD)2008/02/15/
ISBN Number0006-4971
KeywordsAntig, 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