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    • br Author Contributions br Conflict of

    2018-10-23


    Author Contributions
    Conflict of Interest
    Acknowledgments and Role of the Funding Source This work was supported in part by the Chinese National Key Basic Research Project 973 Grant 2013CB966800, the Mega-projects of Science Research for the 12th Five-Year Plan (2013ZX09303302), the State Key Laboratories Project of Excellence Grant (81123005),the Ministry of Health Grant 201202003, the National Natural Science Foundation of China (81370653), the National Clinical research Base construction Projects of Traditional Medicine (2012H01), and Samuel Waxman Cancer Research Foundation Co-PI Program. We are grateful to Shu-Min Xiong for performing the hematological morphological analysis.
    Introduction Over the past decade, numerous studies have highlighted the central role of short non-coding transcripts, named microRNAs (miRNAs), in the pathogenesis of CLL and their influence on the development of the disease and its aggressiveness (Fabbri et al., 2011). MiRNAs are non-coding RNAs which target messenger RNA for degradation and translational repression, and are involved in many physiologic and pathologic processes (Calin and Croce, 2009). A model of CLL pathogenesis that accounts for three of the most frequent recurrent chromosomal abnormalities in B-CLL (13q-, 11q- and 17p-) has been developed explaining the complex interaction networks composed of coding and non-coding genes (Fabbri and Croce, 2011). The clinical course of CLL is highly heterogeneous; some patients have indolent disease never requiring treatment, whereas others need treatment at the time of disease presentation. Several prognostic markers have been identified including genomic abnormalities according to fluorescent in situ hybridization (FISH) (Dohner et al., 2000), immunoglobulin heavy chain variable gene (IGHV) mutation status (Hamblin et al., 1999; Damle et al., 1999), CD38 (Damle et al., 1999) and ZAP70 Exendin-3 (9-39) amide Supplier (Crespo et al., 2003). The prognostic value of biological markers relies on the ability to predict time to first treatment, response to treatment, progression free survival and overall survival (OS). Recently, our group found that a microRNA, miR-155, was expressed at high levels in B-cells from patients with CLL compared with B-cells from normal individuals and in plasma of patients who failed to achieve a complete response compared to responding patients, suggesting its role as a biomarker for risk of progression (Ferrajoli et al., 2013). Several studies have investigated the role played by the Epstein–Barr Virus (EBV) and other viruses in the pathogenesis of CLL (Tsimberidou et al., 2006; Tarrand et al., 2010), but a definitive mechanism involving EBV proteins or genome has not been identified. EBV is a ubiquitous, human-specific gamma herpes virus, which typically causes subclinical and latent infection of B cells in healthy individuals. It is associated with a variety of B-cell lymphomas that arise in patients with or without overt impairments in cellular immunity (Campo et al., 2011). Interestingly, in EBV-associated lymphomas, the substantial majority of cells show evidence for the presence of EBV genome by in-situ hybridization (ISH) (Delecluse et al., 2007). Three types of EBV latency states have been described in EBV-related lymphomas according to the pattern of EBV nuclear antigen (EBNA) and the latent membrane protein (LMP) expression. Two sets of non-coding RNAs are also expressed in all forms of EBV infection: the EBER RNAs (Arrand and Rymo, 1982; Lerner et al., 1981) and the BamHI A rightward transcripts (BARTs). It has been shown that EBV also encodes miRNAs (Cai et al., 2006). EBV miRNAs map to two regions of the viral genome: BHRF1 miRNAs are located immediately upstream and downstream of the BHRF1 open reading frame, while BART miRNAs lie within the intronic regions of BART genes (Amoroso et al., 2011). To date there is little information regarding their functions in the viral and cell life cycle although some specific targets have been identified (Marquitz et al., 2011; Dolken et al., 2010; Barth et al., 2008; Choy et al., 2008; Lo et al., 2007; Lung et al., 2009; Xia et al., 2008). EBV infection may influence the expression of several cellular miRNAs (Navarro et al., 2008). Interestingly, it has been reported that miR-155 is the cellular miRNA most highly induced after EBV infection of lymphoblastoid B-cells (Linnstaedt et al., 2010).