title: Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma.
abstract: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma and can be separated into two subtypes based upon molecular features with similarities to germinal centre B-cells (GCB-like) or activated B-cells (ABC-like). Here we identify gain of 3q27.2 as being significantly associated with adverse outcome in DLBCL and linked with the ABC-like subtype. This lesion includes the BCL6 oncogene, but does not alter BCL6 transcript levels or target-gene repression. Separately, we identify expression of BCL6 in a subset of human haematopoietic stem/progenitor cells (HSPCs). We therefore hypothesize that BCL6 may act by 'hit-and-run' oncogenesis. We model this hit-and-run mechanism by transiently expressing Bcl6 within murine HSPCs, and find that it causes mature B-cell lymphomas that lack Bcl6 expression and target-gene repression, are transcriptionally similar to post-GCB cells, and show epigenetic changes that are conserved from HSPCs to mature B-cells. Together, these results suggest that BCL6 may function in a 'hit-and-run' role in lymphomagenesis.
authors.affiliation: 1] Divisions of Oncology and Hematology, Department of Medicine, School of Medicine, Stanford University, Stanford, California 94305, USA [2].
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
authors.affiliation: 1] Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, 37007 Salamanca, Spain [2] Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain [3].
authors.forename: Carolina
authors.initials: C
authors.lastname: Vicente-Dueñas
authors.affiliation: 1] Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, 37007 Salamanca, Spain [2] Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Romero-Camarero
authors.affiliation: Divisions of Oncology and Hematology, Department of Medicine, School of Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Chih
authors.initials: C
authors.lastname: Long Liu
authors.affiliation: Divisions of Oncology and Hematology, Department of Medicine, School of Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Dai
authors.affiliation: 1] Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, 37007 Salamanca, Spain [2] Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: González-Herrero
authors.affiliation: 1] Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, 37007 Salamanca, Spain [2] Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain.
authors.forename: Idoia
authors.initials: I
authors.lastname: García-Ramírez
authors.affiliation: 1] Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, 37007 Salamanca, Spain [2] Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Alonso-Escudero
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Javeed
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.affiliation: Centro de Biología Molecular Severo Ochoa, CSIC/Universidad Autónoma de Madrid, c/Nicolás Cabrera, n° 1, Campus de Cantoblanco, 28049 Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Campos-Sanchez
authors.affiliation: Servicio de Citometría and Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Orfao
authors.affiliation: Genetically Engineered Mouse Facility, CNB-CSIC, 28006 Madrid, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Pintado
authors.affiliation: 1] Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain [2] Departamento de Anatomía Patológica, Universidad de Salamanca, 37007 Salamanca, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Flores
authors.affiliation: Departamento de Anatomía Patológica, Universidad de Salamanca, 37007 Salamanca, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Blanco
authors.affiliation: 1] Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain [2] Departamento de Fisiología y Farmacología, Universidad de Salamanca, Campus M. Unamuno s/n, 37007 Salamanca, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Jiménez
authors.affiliation: Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
authors.forename: Jose Angel
authors.initials: JA
authors.lastname: Martínez-Climent
authors.affiliation: Departamento de Cirugía, Universidad de Salamanca, 37007 Salamanca, Spain.
authors.forename: Francisco Javier García
authors.initials: FJ
authors.lastname: Criado
authors.affiliation: Departamento de Cirugía, Universidad de Salamanca, 37007 Salamanca, Spain.
authors.forename: María Begoña García
authors.initials: MB
authors.lastname: Cenador
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, 94305 USA.
authors.forename: Shuchun
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, 94305 USA.
authors.forename: Yasodha
authors.initials: Y
authors.lastname: Natkunam
authors.affiliation: Division of Hematology-Oncology, University of Miami, Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA.
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
authors.affiliation: Divisions of Oncology and Hematology, Department of Medicine, School of Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
authors.affiliation: Departments of Medicine and Pharmacology, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Centro de Biología Molecular Severo Ochoa, CSIC/Universidad Autónoma de Madrid, c/Nicolás Cabrera, n° 1, Campus de Cantoblanco, 28049 Madrid, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Cobaleda
authors.affiliation: 1] Divisions of Oncology and Hematology, Department of Medicine, School of Medicine, Stanford University, Stanford, California 94305, USA [2].
authors.forename: Ash A
authors.initials: AA
authors.lastname: Alizadeh
authors.affiliation: 1] Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, 37007 Salamanca, Spain [2] Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain [3].
authors.forename: Isidro
authors.initials: I
authors.lastname: Sánchez-García
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000378:metabolism*; D003520:Cyclophosphamide / Q000627:therapeutic use; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004317:Doxorubicin / Q000627:therapeutic use; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D051560:Proto-Oncogene Proteins c-bcl-6; D000069283:Rituximab; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; C084103:BCL6 protein, human; C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone