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Cancer Cell. 2013 Jun 10;23(6):826-38. doi: 10.1016/j.ccr.2013.05.002.

SYK inhibition modulates distinct PI3K/AKT- dependent survival pathways and cholesterol biosynthesis in diffuse large B cell lymphomas.

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1
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.

Abstract

B cell receptor (BCR) signaling pathway components represent promising treatment targets in diffuse large B cell lymphoma (DLBCL) and additional B cell tumors. BCR signaling activates spleen tyrosine kinase (SYK) and downstream pathways including PI3K/AKT and NF-κB. In previous studies, chemical SYK blockade selectively decreased BCR signaling and induced apoptosis of BCR-dependent DLBCLs. Herein, we characterize distinct SYK/PI3K-dependent survival pathways in DLBCLs with high or low baseline NF-κB activity including selective repression of the pro-apoptotic HRK protein in NF-κB-low tumors. We also define SYK/PI3K-dependent cholesterol biosynthesis as a feed-forward mechanism of maintaining the integrity of BCRs in lipid rafts in DLBCLs with low or high NF-κB. In addition, SYK amplification and PTEN deletion are identified as selective genetic alterations in primary "BCR"-type DLBCLs.

PMID:
23764004
PMCID:
PMC3700321
DOI:
10.1016/j.ccr.2013.05.002
[Indexed for MEDLINE]
Free PMC Article
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