SYK Inhibition Modulates Distinct PI3K/AKT- Dependent Survival Pathways and Cholesterol Biosynthesis in Diffuse Large B Cell Lymphomas

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. •SYK/PI3K inhibition decreases NF-κB activity in DLBCLs with high basal NF-κB•SYK/PI3K blockade induces HRK-dependent apoptosis in DLBCLs with low basal NF-κB•In all BCR-dependent DLBCLs, SYK/PI3K signaling regulates cholesterol biosynthesis•Primary “BCR” DLBCLs selectively exhibit SYK amplification or PTEN deletion