title: Subtype-specific addiction of the activated B-cell subset of diffuse large B-cell lymphoma to FOXP1.
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.
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Dekker
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712; Department of Chemical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX 78712;
authors.forename: Daechan
authors.initials: D
authors.lastname: Park
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Shaffer
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Holger
authors.initials: H
authors.lastname: Kohlhammer
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;
authors.forename: Wei
authors.initials: W
authors.lastname: Deng
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;
authors.forename: Bum-Kyu
authors.initials: BK
authors.lastname: Lee
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712; Department of Chemical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX 78712;
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Ippolito
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712; Department of Chemical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX 78712;
authors.forename: George
authors.initials: G
authors.lastname: Georgiou
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;
authors.forename: Vishwanath R
authors.initials: VR
authors.lastname: Iyer
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 haleytucker@austin.utexas.edu lstaudt@mail.nih.gov.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712; haleytucker@austin.utexas.edu lstaudt@mail.nih.gov.
authors.forename: Haley O
authors.initials: HO
authors.lastname: Tucker
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D012097:Repressor Proteins / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D012097:Repressor Proteins
keywords: DLBCL; FOXP1; lymphoma