title: miR-28 regulates the germinal center reaction and blocks tumor growth in preclinical models of non-Hodgkin lymphoma.
abstract: Non-Hodgkin lymphoma comprises a variety of neoplasms, many of which arise from germinal center (GC)-experienced B cells. microRNA-28 (miR-28) is a GC-specific miRNA whose expression is lost in numerous mature B-cell neoplasms. Here we show that miR-28 regulates the GC reaction in primary B cells by impairing class switch recombination and memory B and plasma cell differentiation. Deep quantitative proteomics combined with transcriptome analysis identified miR-28 targets involved in cell-cycle and B-cell receptor signaling. Accordingly, we found that miR-28 expression diminished proliferation in primary and lymphoma cells in vitro. Importantly, miR-28 reexpression in human Burkitt (BL) and diffuse large B-cell lymphoma (DLBCL) xenografts blocked tumor growth, both when delivered in viral vectors or as synthetic, clinically amenable, molecules. Further, the antitumoral effect of miR-28 is conserved in a primary murine in vivo model of BL. Thus, miR-28 replacement is uncovered as a novel therapeutic strategy for DLBCL and BL treatment.
authors.affiliation: B Cell Biology Laboratory and.
authors.forename: Nahikari
authors.initials: N
authors.lastname: Bartolomé-Izquierdo
authors.affiliation: B Cell Biology Laboratory and.
authors.forename: Virginia G
authors.identifier: 0000-0002-3785-5868
authors.initials: VG
authors.lastname: de Yébenes
authors.affiliation: B Cell Biology Laboratory and.
authors.forename: Angel F
authors.identifier: 0000-0003-0622-2993
authors.initials: AF
authors.lastname: Álvarez-Prado
authors.affiliation: B Cell Biology Laboratory and.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Mur
authors.affiliation: Cardiovascular Proteomics Laboratory, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Juan A
authors.identifier: 0000-0002-9097-6060
authors.initials: JA
authors.lastname: Lopez Del Olmo
authors.affiliation: Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain; and.
authors.forename: Sergio
authors.identifier: 0000-0003-1095-0715
authors.initials: S
authors.lastname: Roa
authors.affiliation: Cardiovascular Proteomics Laboratory, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.|CIBER de Enfermedades Cardiovasculares, Madrid, Spain.
authors.forename: Jesus
authors.identifier: 0000-0003-1461-5092
authors.initials: J
authors.lastname: Vazquez
authors.affiliation: B Cell Biology Laboratory and.
authors.forename: Almudena R
authors.identifier: 0000-0002-7539-3844
authors.initials: AR
authors.lastname: Ramiro
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002051:Burkitt Lymphoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002454:Cell Differentiation; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D018858:Germinal Center / Q000276:immunology* / Q000473:pathology; D006801:Humans; D017578:Immunoglobulin Class Switching; D007156:Immunologic Memory; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology; D040901:Proteomics; D059467:Transcriptome; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C570628:MIRN28 microRNA, human; D035683:MicroRNAs