SYK-dependent Tonic B-cell Signaling is a Rational Treatment Target in Diffuse Large B-cell Lymphoma

Blood, 111(4): 2230-2237, 2008. Published: 2008.02.14

Linfeng Chen, Stefano Monti, Przemyslaw Juszczynski, Yasumichi Hitoshi, Wen Chen, Jeffery L. Kutok, Margaret A. Shipp

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The role of B-cell receptor (BCR)-mediated survival signals in diffuse large B-cell lymphoma (DLBCL) remains undefined. BCR signaling induces receptor oligomerization and Ig α/β ITAM phosphorylation; thereafter, the protein tyrosine kinase SYK is recruited and activated, initiating downstream events and amplifying the original BCR signal. BCRs also transmit low-level tonic survival signals in the absence of receptor engagement. We previously found that protein tyrosine phosphatase-mediated SYK inactivation induced the apoptosis of DLBCLs, highlighting the potential role of SYK-dependent tonic BCR signaling as a survival mechanism. For these reasons, we assessed the efficacy of a novel ATP-competitive inhibitor of SYK, R406, in an extensive panel of DLBCL cell lines. R406 inhibited the proliferation and induced apoptosis of the majority of these DLBCLs. In all R406-sensitive lines, BCR crosslinking increased the autophosphorylation of SYK525/526 and SYK-dependent phosphorylation of the B-cell linker protein, BLNK, and R406 specifically inhibited these events. Furthermore, the R406-sensitive cell lines exhibited tonic phosphorylation of SYK and BLNK in the absence of BCR crosslinking. In addition, the DLBCL cell lines with an intact BCR signaling pathway and sensitivity to the SYK inhibitor were independently identified as BCR tumors by transcriptional profiling. These data suggest that tonic BCR signaling is an important and potentially targetable survival pathway in some, but not all, DLBCLs and that R406-sensitive DLBCLs can be identified by their transcriptional profiles.