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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2230-2237. Prepublished online as a Blood First Edition Paper on November 15, 2007; DOI 10.1182/blood-2007-07-100115. This Article Full Text Full Text (PDF) Supplemental Methods, Tables and Figure All Versions of this Article: blood-2007-07-100115v1 111/4/2230    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Chen, L. Articles by Shipp, M. A. PubMed PubMed Citation Articles by Chen, L. Articles by Shipp, M. A. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma Linfeng Chen1, Stefano Monti2, Przemyslaw Juszczynski1, John Daley1, Wen Chen1, Thomas E. Witzig3, Thomas M. Habermann3, Jeffery L. Kutok4, and Margaret A. Shipp1 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 2 Broad Institute, Cambridge, MA; 3 Mayo Clinic, Rochester, MN; and 4 Department of Pathology, Brigham and Women's Hospital, Boston, MA 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, Ig/β 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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