title: B-cell differentiation in EBV-positive Burkitt lymphoma is impaired at posttranscriptional level by miRNA-altered expression.
abstract: Endemic, sporadic and HIV-associated Burkitt lymphoma (BL) all have a B-cell phenotype and a MYC translocation, but a variable association with the Epstein-Barr virus (EBV). However, there is still no satisfactory explanation of how EBV participates in the pathogenesis of BL. A recent investigation suggested that EBV-positive and EBV-negative BL have different cells of origin. In particular, according to immunoglobulin gene mutation analysis, EBV-negative BLs may originate from early centroblasts, whereas EBV-positive BLs seem to arise from postgerminal center B cells or memory B cells. The appearance of a germinal center phenotype in EBV-positive cells might thus derive from a block in B-cell differentiation. The exit from the germinal center involves a complex series of events, which require the activation of BLIMP-1, and the consequent downregulation of several target genes. Here, we investigated the expression of specific miRNAs predicted to be involved in B-cell differentiation and found that hsa-miR-127 is differentially expressed between EBV-positive and EBV-negative BLs. In particular, it was strongly upregulated only in EBV-positive BL samples, whereas EBV-negative cases showed levels of expression similar to normal controls, including microdissected germinal centers (GC) cells. In addition, we found evidence that hsa-miR-127 is involved in B-cell differentiation process through posttranscriptional regulation of BLIMP1 and XBP1. The overexpression of this miRNA may thus represent a key event in the lymphomagenesis of EBV positive BL, by blocking the B-cell differentiation process.
authors.affiliation: Department of Human Pathology and Oncology, University of Siena, 53100 Siena, Italy. leoncinil@unisi.it
authors.forename: Eleonora
authors.initials: E
authors.lastname: Leucci
authors.forename: Anna
authors.initials: A
authors.lastname: Onnis
authors.forename: Mario
authors.initials: M
authors.lastname: Cocco
authors.forename: Giulia
authors.initials: G
authors.lastname: De Falco
authors.forename: Francesco
authors.initials: F
authors.lastname: Imperatore
authors.forename: Antonicelli
authors.initials: A
authors.lastname: Giuseppina
authors.forename: Valentina
authors.initials: V
authors.lastname: Costanzo
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cerino
authors.forename: Susanna
authors.initials: S
authors.lastname: Mannucci
authors.forename: Rocco
authors.initials: R
authors.lastname: Cantisani
authors.forename: Joshua
authors.initials: J
authors.lastname: Nyagol
authors.forename: Walter
authors.initials: W
authors.lastname: Mwanda
authors.forename: Robert
authors.initials: R
authors.lastname: Iriso
authors.forename: Martin
authors.initials: M
authors.lastname: Owang
authors.forename: Karin
authors.initials: K
authors.lastname: Schurfeld
authors.forename: Cristiana
authors.initials: C
authors.lastname: Bellan
authors.forename: Stefano
authors.initials: S
authors.lastname: Lazzi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Leoncini
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D004854:Herpesvirus 4, Human / Q000254:growth & development; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012323:RNA Processing, Post-Transcriptional; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C547276:MIRN127 microRNA, human; D035683:MicroRNAs; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1