Sequence Analysis in the BLYS and APRIL Receptor TACI Reveals Novel Variants with a Potential Pathogenetic Role in Waldenstrom’s Macroglobulinemia (WM).

B-lymphocyte stimulator protein (BLYS) and a proliferation inducing ligand (APRIL) are members of the tumor necrosis family of ligands which play an important role in normal and malignant human B-cell homeostasis through their receptors BCMA, TACI (for BLYS and APRIL) and BAFF-R (for BLYS only). We previously demonstrated via multicolor flow cytometric and RT-PCR analysis the expression of BLYS and APRIL, along with BCMA, TACI and BAFF-R on lymphoplasmacytic cells (LPC) as well as mast cells, which provide LPC growth support in patients with Waldenstrom’s Macroglobulinemia (WM) (Blood 104:917a). Based on these studies, we performed sequence analysis for BLYS, APRIL, BCMA, TACI and BAFF-R from DNA obtained from CD19⁺ selected bone marrow LPC from 15 patients with the consensus panel diagnosis of WM, who also demonstrated active disease. These studies demonstrated multiple variants in exons 3 and 5 of TACI in 5/15 patients, and exon 1 of BAFF-R in 2/15 patients. The finding of genetic variants in the TACI gene in WM patients is of particular interest given its recently described role as a potential tumor suppressor gene, and potential involvement in the generation of autoimmunity (