Subtype-specific addiction of the activated B-cell subset of diffuse large B-cell lymphoma to FOXP1

Joseph D. Dekker, Daechan Park, Arthur L. Shaffer, Holger Kohlhammer, Wei Deng, Bum Kyu Lee, Gregory C. Ippolito, George Georgiou, Vishwanath R. Iyer, Louis M. Staudt, Haley O. Tucker

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

High expression of the forkhead box P1 (FOXP1) transcription factor distinguishes the aggressive activated B cell (ABC) diffuse large B-cell lymphoma (DLBCL) subtype from the better prognosis germinal center B-cell (GCB)-DLBCL subtype and is highly correlated with poor outcomes. A genetic or functional role for FOXP1 in lymphomagenesis, however, remains unknown. Here, we report that sustained FOXP1 expression is vital for ABC-DLBCL cell-line survival. Genome-wide analyses revealed direct and indirect FOXP1 transcriptional enforcement of ABC-DLBCL hallmarks, including the classical NF-κB and MYD88 (myeloid differentiation primary response gene 88) pathways. FOXP1 promoted gene expression underlying transition of the GCB cell to the plasmablast-the transient B-cell stage targeted in ABC-DLBCL transformation-by antagonizing pathways distinctive of GCB-DLBCL, including that of the GCB "master regulator," BCL6 (B-cell lymphoma 6). Cell-line derived FOXP1 target genes that were highly correlated with FOXP1 expression in primary DLBCL accurately segregated the corresponding clinical subtypes of a large cohort of primary DLBCL isolates and identified conserved pathways associated with ABC-DLBCL pathology.

Original languageEnglish (US)
Pages (from-to)E577-E586
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number5
DOIs
StatePublished - Feb 2 2016

Keywords

  • DLBCL
  • FOXP1
  • Lymphoma

ASJC Scopus subject areas

  • General

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