TACI expression is associated with a mature bone marrow plasma cell signature and C-MAF overexpression in human myeloma cell lines.
OBJECTIVE
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: TACIhighMM cells resemble bone marrow plasma cells and TACIlow 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 beta7. 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 beta7 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 beta7 gene expression, (iii) nucleofection of siRNA to c-maf decreases c-maf mRNA levels and reduces the expression of cyclin D2 and integrin beta7 gene expressions, without affecting TACI expression


CONCLUSIONS
We conclude that TACI activation can upregulate c-maf expression which, in turn, controls cyclin D2, and integrin beta7 gene expression.
Moreaux
Jérôme
J
CHU Montpellier, Institute of Research in Biotherapy, Montpellier, France.
Hose
Dirk
D
Jourdan
Michel
M
Reme
Thierry
T
Hundemer
Michael
M
Moos
Marion
M
Robert
Nicolas
N
Moine
Philippe
P
De Vos
John
J
Goldschmidt
Hartmut
H
Klein
Bernard
B
D001853:Bone Marrow; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039641:Integrin beta Chains / Q000235:genetics; D009101:Multiple Myeloma / Q000473:pathology*; D010950:Plasma Cells / Q000166:cytology*; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics*; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism*
C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D039641:Integrin beta Chains; C495607:MAF protein, human; D051257:Proto-Oncogene Proteins c-maf; C108467:TNFRSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; C091368:integrin beta7