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.
Burkitt lymphoma miR-17-92 cluster MYC Bim miR-17 and miR-20a family Prognosis
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We are grateful to all the clinicians who followed the patients included in the study. This work was supported by grants from Instituto Nacional de Ciência e Tecnologia (INCT) para Controle do Câncer: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) 573806/2008-0/FAPERJ E26/170.026/2008, Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) E-26/110.238/2014—PPSUS, Programa de Oncobiologia/Fundação do Câncer, and FAPERJ E-26/110.375/2014. SWISS-BRIDGE Foundation, sub-project 1B/2014. MCR and RSF had a scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-PDSE) and Ministério da Saúde/INCA, respectively.
Compliance with ethical standards
The study was approved by the institutional ethics committee (registration number 18/09), in accordance with the Declaration of Helsinki.
Conflict of interest
The authors declare that they have no conflict of interest.
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