Virus-encoded microRNA contributes to the molecular profile of EBV-positive Burkitt lymphomas
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Pier Paolo Piccaluga1, Mohsen Navari1,2, Giulia De Falco2,3, Maria Raffaella Ambrosio2, Stefano Lazzi2, Fabio Fuligni1, Cristiana Bellan2, Maura Rossi1, Maria Rosaria Sapienza1, Maria Antonella Laginestra1, Maryam Etebari1, Emily A. Rogena4, Lynnette Tumwine5, Claudio Tripodo6, Davide Gibellini7, Jessica Consiglio8, Carlo M. Croce8, Stefano A. Pileri9, Lorenzo Leoncini2
1Hematopathology Section, Department of Experimental, Diagnostic, and Experimental Medicine, S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy
2Department of Medical Biotechnology, University of Siena, Siena, Italy
3School of Biological and Chemical Sciences, Queen Mary University of London, London, UK
4Department of Pathology, University of Nairobi, Nairobi, Kenya
5Department of Pathology, Makerere University, Kampala, Uganda
6Tumour Immunology Unit, Department of Health Science, Human Pathology Section, Palermo University School of Medicine, Palermo, Italy
7Department of Pathology and Diagnostic, University of Verona, Verona, Italy
8Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
9Diagnostic Hematopathology Unit, European Institute of Oncology, Milan, Italy
Pier Paolo Piccaluga, e-mail: [email protected]
Keywords: Burkitt lymphoma, miRNA, BART6, EBV, pathogenesis
Received: June 04, 2015 Accepted: July 20, 2015 Published: July 31, 2015
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.
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