Transcriptional repression of plasma cell differentiation is orchestrated by aberrant over‐expression of the ETS factor SPIB in Waldenström macroglobulinaemia. (7th May 2014)

• Record Type: Journal Article
• Authors: Zhou, Yangsheng; Liu, Xia; Xu, Lian; Hunter, Zachary R.; Cao, Yang; Yang, Guang; Carrasco, Ruben; Treon, Steven P.
• Is Part Of: British journal of haematology. Volume 166:Number 5(2014:Sep.)
• Page Start: 677
• Page End: 689
• Publication Date: 2014-05-07
• Subjects: Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.12936
• Languages: English
• ISSNs: 0007-1048

Abstract

<abstract abstract-type="main" id="bjh12936-abs-0001"> <title>Summary</title> <p>In Waldenström macroglobulinaemia (WM), the mechanism(s) responsible for repression of B‐cell differentiation remains unknown. We found that expression of <italic>SPIB</italic> and <italic>ID</italic><italic>2</italic> were significantly increased and decreased, respectively, in WM lymphoplasmacytic cells (LPC). Ectopic expression of <italic>SPIB</italic> in healthy donor CD19<sup>+</sup> cells inhibited plasmacytic differentiation in conjunction with decreased transcription of <italic>IRF</italic><italic>4</italic> and <italic>XBP</italic><italic>1</italic> spliced form. In primary WM LPC, knock‐down of <italic>SPIB</italic> induced plasmacytic differentiation in conjunction with increased transcription of <italic>PRDM</italic><italic>1</italic>, <italic>XBP</italic><italic>1</italic> spliced form, <italic>IRF</italic><italic>4</italic> and <italic>ID</italic><italic>2</italic>. Knock‐down of <italic>SPIB</italic> also led to decreased <italic>BCL</italic><italic>2</italic> expression. Given that <italic>SPIB</italic> is a direct target of <italic>POU</italic><italic>2</italic><italic>AF</italic><italic>1</italic> (<italic>OBF</italic><italic>1</italic>) in complex with <italic>POU</italic><italic>2</italic><italic>F</italic><italic>2</italic> or <italic>POU</italic><italic>2</italic><italic>F</italic><italic>1</italic>, we next examined their expression in WM LPC. <italic>POU</italic><italic>2</italic><italic>F</italic><italic>2</italic> transcription, as well as POU2F2 and POU2AF1 protein expression was higher in WM LPC. Ectopic expression of <italic>POU</italic><italic>2</italic><italic>F</italic><italic>2</italic> in healthy donor CD19<sup>+</sup> cells induced transcription of <italic>SPIB</italic> and suppressed transcription of <italic>PRDM</italic><italic>1</italic> and <italic>IRF</italic><italic>4</italic>. Chromatin immunoprecipitation analysis in BCWM.1 WM cells confirmed binding of POU2F2 and POU2AF1 in <italic>SPIB</italic> and <italic>ID</italic><italic>2</italic> promoters. These findings establish a molecular hierarchy among <italic>POU</italic><italic>2</italic><italic>F</italic><italic>2</italic>, <italic>SPIB</italic> and <italic>ID</italic><italic>2</italic> during B‐cell differentiation, and suggest that aberrant expression of these transcription factors plays an important role in arresting plasmacytic differentiation in WM.</p> </abstract>