1. Transcriptional repression of plasma cell differentiation is orchestrated by aberrant over-expression of the ETS factor SPIB in Waldenström macroglobulinaemia.
- Author
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Zhou, Yangsheng, Liu, Xia, Xu, Lian, Hunter, Zachary R., Cao, Yang, Yang, Guang, Carrasco, Ruben, and Treon, Steven P.
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B cells ,CELL differentiation ,WALDENSTROM'S macroglobulinemia ,CONNECTIVE tissue cells ,MORPHOGENESIS - Abstract
In Waldenström macroglobulinaemia ( WM), the mechanism(s) responsible for repression of B-cell differentiation remains unknown. We found that expression of SPIB and ID 2 were significantly increased and decreased, respectively, in WM lymphoplasmacytic cells ( LPC). Ectopic expression of SPIB in healthy donor CD19
+ cells inhibited plasmacytic differentiation in conjunction with decreased transcription of IRF 4 and XBP 1 spliced form. In primary WM LPC, knock-down of SPIB induced plasmacytic differentiation in conjunction with increased transcription of PRDM 1, XBP 1 spliced form, IRF 4 and ID 2. Knock-down of SPIB also led to decreased BCL 2 expression. Given that SPIB is a direct target of POU 2 AF 1 ( OBF 1) in complex with POU 2 F 2 or POU 2 F 1, we next examined their expression in WM LPC. POU 2 F 2 transcription, as well as POU2F2 and POU2 AF1 protein expression was higher in WM LPC. Ectopic expression of POU 2 F 2 in healthy donor CD19+ cells induced transcription of SPIB and suppressed transcription of PRDM 1 and IRF 4. Chromatin immunoprecipitation analysis in BCWM.1 WM cells confirmed binding of POU2F2 and POU2 AF1 in SPIB and ID 2 promoters. These findings establish a molecular hierarchy among POU 2 F 2, SPIB and ID 2 during B-cell differentiation, and suggest that aberrant expression of these transcription factors plays an important role in arresting plasmacytic differentiation in WM. [ABSTRACT FROM AUTHOR]- Published
- 2014
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