title: The hematopoietic oncoprotein FOXP1 promotes tumor cell survival in diffuse large B-cell lymphoma by repressing S1PR2 signaling.
abstract: Aberrant expression of the oncogenic transcription factor forkhead box protein 1 (FOXP1) is a common feature of diffuse large B-cell lymphoma (DLBCL). We have combined chromatin immunoprecipitation and gene expression profiling after FOXP1 depletion with functional screening to identify targets of FOXP1 contributing to tumor cell survival. We find that the sphingosine-1-phosphate receptor 2 (S1PR2) is repressed by FOXP1 in activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL cell lines with aberrantly high FOXP1 levels; S1PR2 expression is further inversely correlated with FOXP1 expression in 3 patient cohorts. Ectopic expression of wild-type S1PR2, but not a point mutant incapable of activating downstream signaling pathways, induces apoptosis in DLBCL cells and restricts tumor growth in subcutaneous and orthotopic models of the disease. The proapoptotic effects of S1PR2 are phenocopied by ectopic expression of the small G protein Gα13 but are independent of AKT signaling. We further show that low S1PR2 expression is a strong negative prognosticator of patient survival, alone and especially in combination with high FOXP1 expression. The S1PR2 locus has previously been demonstrated to be recurrently mutated in GCB DLBCL; the transcriptional silencing of S1PR2 by FOXP1 represents an alternative mechanism leading to inactivation of this important hematopoietic tumor suppressor.
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland;
authors.forename: Michael
authors.initials: M
authors.lastname: Flori
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland;
authors.forename: Corina A
authors.initials: CA
authors.lastname: Schmid
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland;
authors.forename: Eric T
authors.initials: ET
authors.lastname: Sumrall
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland; and.
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Institute of Molecular Life Sciences and SIB Swiss Institute of Bioinformatics, University of Zürich, Zürich, Switzerland.
authors.forename: Charity W
authors.initials: CW
authors.lastname: Law
authors.affiliation: Institute of Molecular Life Sciences and SIB Swiss Institute of Bioinformatics, University of Zürich, Zürich, Switzerland.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Robinson
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland;
authors.forename: Anne
authors.initials: A
authors.lastname: Müller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center / Q000473:pathology; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000145:classification / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D051379:Mice; D009363:Neoplasm Proteins / Q000502:physiology*; D009368:Neoplasm Transplantation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D049349:Receptors, Lysosphingolipid / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid; D012097:Repressor Proteins; C477522:S1PR2 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D044365:GTP-Binding Protein alpha Subunits, G12-G13