Virus-encoded microRNA contributes to the molecular profile of EBV-positive Burkitt lymphomas

// Pier Paolo Piccaluga 1 , Mohsen Navari 1, 2 , Giulia De Falco 2, 3 , Maria Raffaella Ambrosio 2 , Stefano Lazzi 2 , Fabio Fuligni 1 , Cristiana Bellan 2 , Maura Rossi 1 , Maria Rosaria Sapienza 1 , Maria Antonella Laginestra 1 , Maryam Etebari 1 , Emily A. Rogena 4 , Lynnette Tumwine 5 , Claudio Tripodo 6 , Davide Gibellini 7 , Jessica Consiglio 8 , Carlo M. Croce 8 , Stefano A. Pileri 9 , Lorenzo Leoncini 2 1 Hematopathology Section, Department of Experimental, Diagnostic, and Experimental Medicine, S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy 2 Department of Medical Biotechnology, University of Siena, Siena, Italy 3 School of Biological and Chemical Sciences, Queen Mary University of London, London, UK 4 Department of Pathology, University of Nairobi, Nairobi, Kenya 5 Department of Pathology, Makerere University, Kampala, Uganda 6 Tumour Immunology Unit, Department of Health Science, Human Pathology Section, Palermo University School of Medicine, Palermo, Italy 7 Department of Pathology and Diagnostic, University of Verona, Verona, Italy 8 Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA 9 Diagnostic Hematopathology Unit, European Institute of Oncology, Milan, Italy Correspondence to: Pier Paolo Piccaluga, e-mail: pierpaolo.piccaluga@unibo.it Keywords: Burkitt lymphoma, miRNA, BART6, EBV, pathogenesis Received: June 04, 2015      Accepted: July 20, 2015      Published: July 31, 2015 ABSTRACT Burkitt lymphoma (BL) is an aggressive neoplasm characterized by consistent morphology and phenotype, typical clinical behavior and distinctive molecular profile. The latter is mostly driven by the MYC over-expression associated with the characteristic translocation (8;14) (q24; q32) or with variant lesions. Additional genetic events can contribute to Burkitt Lymphoma pathobiology and retain clinical significance. A pathogenetic role for Epstein-Barr virus infection in Burkitt lymphomagenesis has been suggested; however, the exact function of the virus is largely unknown. In this study, we investigated the molecular profiles (genes and microRNAs) of Epstein-Barr virus-positive and -negative BL, to identify specific patterns relying on the differential expression and role of Epstein-Barr virus-encoded microRNAs. First, we found significant differences in the expression of viral microRNAs and in selected target genes. Among others, we identified LIN28B , CGNL1, GCET2 , MRAS , PLCD4 , SEL1L , SXX1, and the tyrosine kinases encoding STK10 / STK33 , all provided with potential pathogenetic significance. GCET2, also validated by immunohistochemistry, appeared to be a useful marker for distinguishing EBV-positive and EBV-negative cases. Further, we provided solid evidences that the EBV-encoded microRNAs (e.g. BART6) significantly mold the transcriptional landscape of Burkitt Lymphoma clones. In conclusion, our data indicated significant differences in the transcriptional profiles of EBV-positive and EBV-negative BL and highlight the role of virus encoded miRNA.