Epstein-Barr Virus MicroRNAs are Expressed in Patients with Chronic Lymphocytic Leukemia and Correlate with Overall Survival

Alessandra Ferrajoli, Cristina Ivan, Maria Ciccone, Masayoshi Shimizu, Yoshiaki Kita, Masahisha Ohtsuka, Lucilla D'Abundo, Jun Qiang, Susan Lerner, Nazila Nouraee, Kari G. Rabe, Laura Z. Rassenti, Katrien Van Roosbroeck, John T. Manning, Yuan Yuan, Xinna Zhang, Tait D. Shanafelt, William G. Wierda, Silvia Sabbioni, Jeffrey J. TarrandZeev Estrov, Milan Radovich, Han Liang, Massimo Negrini, Thomas J. Kipps, Neil E. Kay, Michael Keating, George A. Calin

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Although numerous studies highlighted the role of Epstein-Barr Virus (EBV) in B-cell transformation, the involvement of EBV proteins or genome in the development of the most frequent adult leukemia, chronic lymphocytic leukemia (CLL), has not yet been defined. We hypothesized that EBV microRNAs contribute to progression of CLL and demonstrated the presence of EBV miRNAs in B-cells, in paraffin-embedded bone marrow biopsies and in the plasma of patients with CLL by using three different methods (small RNA-sequencing, quantitative reverse transcription PCR [q-RT-PCR] and miRNAs in situ hybridization [miRNA-ISH]). We found that EBV miRNA BHRF1-1 expression levels were significantly higher in the plasma of patients with CLL compared with healthy individuals (p. <. 0. ·. 0001). Notably, BHRF1-1 as well as BART4 expression were detected in the plasma of either seronegative or seropositive (anti-EBNA-1 IgG and EBV DNA tested) patients; similarly, miRNA-ISH stained positive in bone marrow specimens while LMP1 and EBER immunohistochemistry failed to detect viral proteins and RNA. We also found that BHRF1-1 plasma expression levels were positively associated with elevated beta-2-microglobulin levels and advanced Rai stages and observed a correlation between higher BHRF1-1 expression levels and shorter survival in two independent patients' cohorts. Furthermore, in the majority of CLL cases where BHRF1-1 was exogenously induced in primary malignant B cells the levels of TP53 were reduced. Our findings suggest that EBV may have a role in the process of disease progression in CLL and that miRNA RT-PCR and miRNAs ISH could represent additional methods to detect EBV miRNAs in patients with CLL.

Original languageEnglish (US)
Pages (from-to)572-582
Number of pages11
JournalEBioMedicine
Volume2
Issue number6
DOIs
StatePublished - Jun 1 2015

Keywords

  • BHRF1-1
  • Chronic lymphocytic leukemia
  • Epstein-Barr Virus
  • MiRNAs
  • Overall survival

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Ferrajoli, A., Ivan, C., Ciccone, M., Shimizu, M., Kita, Y., Ohtsuka, M., D'Abundo, L., Qiang, J., Lerner, S., Nouraee, N., Rabe, K. G., Rassenti, L. Z., Van Roosbroeck, K., Manning, J. T., Yuan, Y., Zhang, X., Shanafelt, T. D., Wierda, W. G., Sabbioni, S., ... Calin, G. A. (2015). Epstein-Barr Virus MicroRNAs are Expressed in Patients with Chronic Lymphocytic Leukemia and Correlate with Overall Survival. EBioMedicine, 2(6), 572-582. https://doi.org/10.1016/j.ebiom.2015.04.018