Transcription factors Xbp-1, Blimp-1, and BSAP are involved in the regulation of plasmacytic differentiation induced by 2-methoxyestradiol in myeloma cell lines

Abstract

Our previous studies demonstrated that a low concentration of 2-methoxyestradiol (2ME2) could induce the differentiation of myeloma cell lines and CD138+ primary myeloma cells from myeloma patients and up-regulate the expression of messenger RNA (mRNA) and protein for the gene encoding X-box binding protein 1 (Xbp-1) in myeloma cell lines. In the present study, we used phosphorothioated antisense oligodeoxynucleotides (ASODN) to investigate the roles and interactions of transcription factors Xbp-1, B-lymphocyte induced maturation protein 1 (Blimp-1), and PAX-5-encoded B-cell-specific activator protein (BSAP), which are thought to be involved in the regulation of B-lymphocytic or plasmacytic differentiation. Blimp-1 ASODN and Xbp-1 ASODN clearly inhibited myeloma cell differentiation and significantly partially inhibited the differentiation effects induced by 2ME2 at low concentration, whereas PAX-5 ASODN clearly induced myeloma cell differentiation and significantly enhanced 2ME2-induced differentiation effects. Moreover, after incubation with Blimp-1 ASODN, the level of Xbp-1 mRNA clearly declined, whereas the level of PAX-5 mRNA significantly increased in myeloma cells. These results demonstrate that transcription factors Xbp-1, Blimp-1, and PAX-5-encoded BSAP play important roles in the regulation of plasmacytic differentiation and exert their effects on differentiation induced by low 2ME2 concentrations. Our primary study provided the rationale for a promising strategy-the future application of transcription-factor ASODN for clinical patients.