NF-κB determines how SYK and PI3K inhibitors induce apoptosis in B cell receptor–dependent DLBCL.
Major finding: NF-κB determines how SYK and PI3K inhibitors induce apoptosis in B cell receptor–dependent DLBCL.
Mechanism: SYK/PI3K inhibition decreases BCL2A1 expression in NF-κB–high DLBCL and induces HRK in NF-κB–low DLBCL.
Impact: Characterizing subtype-specific effects of SYK/PI3K inhibition may identify additional therapeutic targets.
Hyperactive B-cell receptor (BCR) signaling promotes the survival of some B-cell malignancies, including certain subtypes of diffuse large B-cell lymphoma (DLBCL). Downstream BCR effectors, including spleen tyrosine kinase (SYK) and phosphoinositide 3-kinase (PI3K), thus represent attractive therapeutic targets for these cancers, and small-molecule SYK inhibitors have shown preclinical and clinical activity in DLBCL. A better understanding of how these inhibitors work in DLBCL subtypes could help guide use of BCR-targeted therapy and potentially identify additional therapeutic targets in the BCR pathway. Chen and colleagues found that SYK/PI3K inhibition inhibited the growth of BCR-dependent DLBCL cell lines with high or low baseline NF-κB activity. In DLBCLs with high NF-κB activity, inhibition of SYK or downstream PI3K signaling significantly reduced the expression of NF-κB target genes, including antiapoptotic BCL2 family members such as BCL2A1. In contrast, SYK or PI3K inhibition in DLBCLs with low NF-κB activity led to upregulation of the proapoptotic BCL2 family member HRK. SYK or PI3K inhibition also downregulated components of the cholesterol biosynthesis pathway in both NF-κB–high and NF-κB–low BCR-dependent DLBCLs, which was notable because BCR signaling is dependent on the association of BCR clusters with cholesterol-rich lipid rafts in the cell membrane. Indeed, SYK inhibition specifically reduced membrane cholesterol content and disrupted BCR localization to lipid rafts in BCR-dependent DLBCL cells. Together with the finding that BCR-dependent DLBCLs are more likely to have amplification of SYK or deletion of PTEN, which encodes a negative regulator of PI3K signaling, these findings provide insight into the role of SYK and PI3K in BCR-mediated survival in DLBCL and may guide the development of inhibitors of proximal BCR signaling in DLBCL subtypes.