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Epstein–Barr Virus MicroRNAs are Expressed in Patients with Chronic Lymphocytic Leukemia and Correlate with Overall Survival()
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 cont...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535165/ https://www.ncbi.nlm.nih.gov/pubmed/26288818 http://dx.doi.org/10.1016/j.ebiom.2015.04.018 |
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author | Ferrajoli, Alessandra Ivan, Cristina Ciccone, Maria Shimizu, Masayoshi Kita, Yoshiaki Ohtsuka, Masahisha D'Abundo, Lucilla Qiang, Jun Lerner, Susan Nouraee, Nazila Rabe, Kari G. Rassenti, Laura Z. Van Roosbroeck, Katrien Manning, John T. Yuan, Yuan Zhang, Xinna Shanafelt, Tait D. Wierda, William G. Sabbioni, Silvia Tarrand, Jeffrey J. Estrov, Zeev Radovich, Milan Liang, Han Negrini, Massimo Kipps, Thomas J. Kay, Neil E. Keating, Michael Calin, George A. |
author_facet | Ferrajoli, Alessandra Ivan, Cristina Ciccone, Maria Shimizu, Masayoshi Kita, Yoshiaki Ohtsuka, Masahisha D'Abundo, Lucilla Qiang, Jun Lerner, Susan Nouraee, Nazila Rabe, Kari G. Rassenti, Laura Z. Van Roosbroeck, Katrien Manning, John T. Yuan, Yuan Zhang, Xinna Shanafelt, Tait D. Wierda, William G. Sabbioni, Silvia Tarrand, Jeffrey J. Estrov, Zeev Radovich, Milan Liang, Han Negrini, Massimo Kipps, Thomas J. Kay, Neil E. Keating, Michael Calin, George A. |
author_sort | Ferrajoli, Alessandra |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4535165 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-45351652015-08-18 Epstein–Barr Virus MicroRNAs are Expressed in Patients with Chronic Lymphocytic Leukemia and Correlate with Overall Survival() Ferrajoli, Alessandra Ivan, Cristina Ciccone, Maria Shimizu, Masayoshi Kita, Yoshiaki Ohtsuka, Masahisha D'Abundo, Lucilla Qiang, Jun Lerner, Susan Nouraee, Nazila Rabe, Kari G. Rassenti, Laura Z. Van Roosbroeck, Katrien Manning, John T. Yuan, Yuan Zhang, Xinna Shanafelt, Tait D. Wierda, William G. Sabbioni, Silvia Tarrand, Jeffrey J. Estrov, Zeev Radovich, Milan Liang, Han Negrini, Massimo Kipps, Thomas J. Kay, Neil E. Keating, Michael Calin, George A. EBioMedicine Original Article 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. Elsevier 2015-04-29 /pmc/articles/PMC4535165/ /pubmed/26288818 http://dx.doi.org/10.1016/j.ebiom.2015.04.018 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Ferrajoli, Alessandra Ivan, Cristina Ciccone, Maria Shimizu, Masayoshi Kita, Yoshiaki Ohtsuka, Masahisha D'Abundo, Lucilla Qiang, Jun Lerner, Susan Nouraee, Nazila Rabe, Kari G. Rassenti, Laura Z. Van Roosbroeck, Katrien Manning, John T. Yuan, Yuan Zhang, Xinna Shanafelt, Tait D. Wierda, William G. Sabbioni, Silvia Tarrand, Jeffrey J. Estrov, Zeev Radovich, Milan Liang, Han Negrini, Massimo Kipps, Thomas J. Kay, Neil E. Keating, Michael Calin, George A. Epstein–Barr Virus MicroRNAs are Expressed in Patients with Chronic Lymphocytic Leukemia and Correlate with Overall Survival() |
title | Epstein–Barr Virus MicroRNAs are Expressed in Patients with Chronic Lymphocytic Leukemia and Correlate with Overall Survival() |
title_full | Epstein–Barr Virus MicroRNAs are Expressed in Patients with Chronic Lymphocytic Leukemia and Correlate with Overall Survival() |
title_fullStr | Epstein–Barr Virus MicroRNAs are Expressed in Patients with Chronic Lymphocytic Leukemia and Correlate with Overall Survival() |
title_full_unstemmed | Epstein–Barr Virus MicroRNAs are Expressed in Patients with Chronic Lymphocytic Leukemia and Correlate with Overall Survival() |
title_short | Epstein–Barr Virus MicroRNAs are Expressed in Patients with Chronic Lymphocytic Leukemia and Correlate with Overall Survival() |
title_sort | epstein–barr virus micrornas are expressed in patients with chronic lymphocytic leukemia and correlate with overall survival() |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535165/ https://www.ncbi.nlm.nih.gov/pubmed/26288818 http://dx.doi.org/10.1016/j.ebiom.2015.04.018 |
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