title: miR-17-92 cluster components analysis in Burkitt lymphoma: overexpression of miR-17 is associated with poor prognosis.
abstract: Burkitt lymphoma (BL) is an aggressive B cell lymphoma characterized by the reciprocal translocation of the c-Myc gene with immunoglobulin genes. Recently, MYC has been shown to maintain the neoplastic state via the miR-17-92 microRNA cluster that suppresses chromatin regulatory genes and the apoptosis regulator Bim. However, the expression and prognostic impact of miR-17-92 members in pediatric BL (pBL) are unknown. Therefore, we investigated miR-17, miR-19a, miR-19b, miR-20, and miR-92a expression and prognostic impact in a series of 41 pBL samples. In addition, Bim protein expression was evaluated and compared to miR-17, miR-19a, miR-19b, miR-20, and miR-92a levels and patient outcomes. The expression of miR-17-92 members was evaluated by qPCR and Bim protein by immunohistochemistry. Log-rank test was employed to assess prognostic impact. We found that upregulated expression of miR-17 and miR-20a correlates with lack of pro-apoptotic Bim expression. Patients bearing tumors with upregulated miR-17 displayed decreased overall survival (OS), and multivariate analysis revealed that miR-17 was a significant predictor of shortened OS. Using hairpin inhibitors, we showed that inhibition of miR-17 resulted in enhanced Bim expression in a BL cell line overexpressing the miR-17-92 cluster. Our results describe for the first time miR-17, miR-19a, miR-19b, miR-20a, and miR-92a expression profiles in pBL. The prognostic impact of miR-17 should be validated in a larger series, and may provide new therapeutic avenues in the era of anti-miRNA therapy research. Additional functional studies are further required to understand the specific role of miR-17-92 cluster members in BL.
authors.affiliation: Programa de Pesquisa em Hemato-Oncologia Molecular, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.|Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Marcela Cristina
authors.initials: MC
authors.lastname: Robaina
authors.affiliation: Programa de Pesquisa em Hemato-Oncologia Molecular, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
authors.forename: Roberta Soares
authors.initials: RS
authors.lastname: Faccion
authors.affiliation: Programa de Pesquisa em Hemato-Oncologia Molecular, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
authors.forename: Luciano
authors.initials: L
authors.lastname: Mazzoccoli
authors.affiliation: Divisão de Patologia, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
authors.forename: Lidia Maria M
authors.initials: LM
authors.lastname: Rezende
authors.affiliation: Consultoria em Patologia, Botucatu, São Paulo, Brazil.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Queiroga
authors.affiliation: Consultoria em Patologia, Botucatu, São Paulo, Brazil.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Bacchi
authors.affiliation: Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Thomas-Tikhonenko
authors.affiliation: Programa de Pesquisa em Hemato-Oncologia Molecular, Instituto Nacional de Câncer, Rio de Janeiro, Brazil. cklumb@inca.gov.br.|Laboratório de Hemato-Oncologia Celular e Molecular, Praça da Cruz Vermelha, 23, 6th floor, Rio de Janeiro, RJ, CEP: 20230-130, Brazil. cklumb@inca.gov.br.
authors.forename: Claudete Esteves
authors.initials: CE
authors.lastname: Klumb
mesh_terms: D000293:Adolescent; D002051:Burkitt Lymphoma / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D011379:Prognosis; D062085:RNA, Long Noncoding
chemical_list: C568997:MIR17HG, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding
keywords: Bim; Burkitt lymphoma; MYC; Prognosis; miR-17 and miR-20a family; miR-17-92 cluster