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

L Chen, S Monti, P Juszczynski, J Ouyang, B Chapuy… - Cancer cell, 2013 - cell.com
Cancer cell, 2013cell.com
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 …
Summary
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.
cell.com