Transcriptional repression of plasma cell differentiation is orchestrated by aberrant over‐expression of the ETS factor SPIB in Waldenström macroglobulinaemia

Summary 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 POU 2F2 and POU 2 AF 1 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 POU 2F2 and POU 2 AF 1 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 .