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TACI expression is associated with a mature bone marrow plasma cell signature and C-MAF overexpression in human myeloma cell lines

From the CHU Montpellier, Institute of Research in Biotherapy, Montpellier, F-34285 France (JM, MJ, NR, PM, JDV, BK); Université Montpellier1, F-34967 France (JDV, BK); INSERM, U847, Montpellier, F-34197 France (JM, MJ, TR, JDV, BK); Medizinische Klinik und Poliklinik V, Universitätsklinikum Heidelberg, INF410, 69120 Heidelberg, Germany (DH, MH, MM, HG)

Correspondence: Bernard Klein, INSERM U475, 99, rue Puech Villa, 34197 Montpellier Cedex 5, France. E-mail: klein{at}montp.inserm.fr

Background and Objectives: BAFF and APRIL stimulate the growth of multiple myeloma (MM) cells. BAFF and APRIL share two receptors – TACI and BCMA – and BAFF binds to a third receptor, BAFF-R. We previously reported that TACI gene expression is bimodal in 18 human MM cell lines (HMCL), being either present or absent, unlike BCMA that is expressed on all HMCL. BAFF-R is lacking. TACI expression is a good indicator of a BAFF-binding receptor in HMCL. In primary MM cells, the level of TACI expression correlates with a characteristic phenotypic pattern: TACI^high MM cells resemble bone marrow plasma cells and TACI^low resemble plasmablasts. The aim of this study was to further characterize the role of TACI expression in MM

Design and Methods: Using gene expression profiling, we investigated whether these patterns are kept in TACI⁺ or TACI^– HMCL.

Results: Eighty genes/EST interrogated by Affymetrix microarrays were differentially expressed between TACI⁺ and TACI^– HMCL, particularly c-maf, cyclin D2, and integrin ß7. Triggered by the finding that TACI and c-maf expressions correlate in TACI⁺ HMCL, we demonstrated that TACI activation influences c-maf expression: (i) activation of TACI by BAFF or APRIL increases c-maf, cyclin D2, and integrin ß7 gene expressions in TACI⁺ HMCL, (ii) blocking of autocrine BAFF/APRIL stimulation in some TACI⁺ HMCL by the TACI-Fc fusion protein reduces c-maf, cyclin D2, and integrin ß7 gene expression, (iii) nucleofection of siRNA to c-maf decreases c-maf mRNA levels and reduces the expression of cyclin D2 and integrin ß7 gene expressions, without affecting TACI expression

Interpretation and Conclusions: We conclude that TACI activation can upregulate c-maf expression which, in turn, controls cyclin D2, and integrin ß7 gene expression.

Key words: myeloma, TACI, gene expression profiles, c-maf.

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