Abstract
Multiple myeloma is an incurable cancer of plasma cells. A single nucleotide variant rs34562254 in the gene encoding TACI (transmembrane activator and CAML interactor), is associated with an increased risk of myeloma. TACI is a B cell receptor that signals through the canonical NF-κB pathway to enhance survival and proliferation of B cells. The TACI variant, which results in a proline to leucine substitution at residue P251L in the long isoform and P205L in the short isoform, is present at high allele frequency in Polynesians.
To investigate a possible reason for the increased risk of multiple myeloma associated with the leucine residue, we designed a luciferase assay that measures NF-κB activity of TACI wild type and the leucine variant after transfection in HEK293FT cells. NF-κB activity driven by TACI-initiated signalling was determined by measuring the transcription of a luciferase reporter. The NF-κB activity was measured with and without stimulation of TACI by its ligand, BAFF (B-cell activating factor).
The key finding of this study was markedly reduced NF-κB activity of the TACI P205L variant compared to the wild type, with a 49% (P < 0.001) and 72% (P < 0.001) reduction in activity without and with BAFF stimulation.
This result, which is the first to identify reduced signalling activity by the TACI P205L variant, suggests a possible indirect effect of TACI P205L on the increased risk of myeloma by reducing NF-κB activity. Future research could include investigations of the interaction between TACI and other proteins of the canonical NF-κB pathway, or investigations of the effect of TACI on germinal centre B cells and the effect of TACI P205L on the non-canonical NF-κB pathway.