Transcription factors Xbp-1, Blimp-1, and BSAP are involved in the regulation of plasmacytic differentiation induced by 2-methoxyestradiol in myeloma cell lines.
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.
Jiang
Hua
H
Department of Hematology, Changzheng Hospital, 415 Fengyang Road, Shanghai, China.
Gao
Weiran
W
Sze
Daniel Man-Yuen
DM
Xiong
Hong
H
Hou
Jian
J
D000077584:2-Methoxyestradiol; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D051757:PAX5 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010950:Plasma Cells / Q000378:metabolism* / Q000473:pathology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins; C508241:SDC1 protein, human; D053668:Syndecan-1; D014157:Transcription Factors; D050257:Tubulin Modulators; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C087042:PRDM1 protein, human; D004958:Estradiol; D000077584:2-Methoxyestradiol; D000074462:Positive Regulatory Domain I-Binding Factor 1