SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma.
In: Blood, Jg. 111 (2008-02-15), Heft 4, S. 2230-7
academicJournal
Zugriff:
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.
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SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma.
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Autor/in / Beteiligte Person: | Chen, L ; Monti, S ; Juszczynski, P ; Daley, J ; Chen, W ; Witzig, TE ; Habermann, TM ; Kutok, JL ; Shipp, MA |
Zeitschrift: | Blood, Jg. 111 (2008-02-15), Heft 4, S. 2230-7 |
Veröffentlichung: | 2021- : [New York] : Elsevier ; <i>Original Publication</i>: New York, Grune & Stratton [etc.], 2008 |
Medientyp: | academicJournal |
ISSN: | 0006-4971 (print) |
DOI: | 10.1182/blood-2007-07-100115 |
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