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.

Chen L, Monti S, Juszczynski P, Ouyang J, Chapuy B, Neuberg D, et al. SYK inhibition modulates distinct PI3K/AKT-dependent survival pathways and cholesterol biosynthesis in diffuse large B cell lymphomas. Cancer Cell 2013;23:826–38.