title: Transcriptional repression of plasma cell differentiation is orchestrated by aberrant over-expression of the ETS factor SPIB in Waldenström macroglobulinaemia.
abstract: In Waldenström macroglobulinaemia (WM), the mechanism(s) responsible for repression of B-cell differentiation remains unknown. We found that expression of SPIB and ID2 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 IRF4 and XBP1 spliced form. In primary WM LPC, knock-down of SPIB induced plasmacytic differentiation in conjunction with increased transcription of PRDM1, XBP1 spliced form, IRF4 and ID2. Knock-down of SPIB also led to decreased BCL2 expression. Given that SPIB is a direct target of POU2AF1 (OBF1) in complex with POU2F2 or POU2F1, we next examined their expression in WM LPC. POU2F2 transcription, as well as POU2F2 and POU2AF1 protein expression was higher in WM LPC. Ectopic expression of POU2F2 in healthy donor CD19(+) cells induced transcription of SPIB and suppressed transcription of PRDM1 and IRF4. Chromatin immunoprecipitation analysis in BCWM.1 WM cells confirmed binding of POU2F2 and POU2AF1 in SPIB and ID2 promoters. These findings establish a molecular hierarchy among POU2F2, SPIB and ID2 during B-cell differentiation, and suggest that aberrant expression of these transcription factors plays an important role in arresting plasmacytic differentiation in WM.
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA, USA; Departments of Medicine and Pathology, Harvard Medical School, Boston, MA, USA.
authors.forename: Yangsheng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.forename: Lian
authors.initials: L
authors.lastname: Xu
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Hunter
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Ruben
authors.initials: R
authors.lastname: Carrasco
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
mesh_terms: D000368:Aged; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D050813:Octamer Transcription Factor-2 / Q000096:biosynthesis / Q000235:genetics; D010950:Plasma Cells / Q000166:cytology / Q000502:physiology*; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D008258:Waldenstrom Macroglobulinemia / Q000097:blood* / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D050813:Octamer Transcription Factor-2; C091546:POU2AF1 protein, human; C058435:POU2F2 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C076877:SPIB protein, human
keywords: POU
  
  1
  
  AF
  
  1; POU
  
  2
  
  F
  
  2; SPIB; waldenström Macroglobulinaemia