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 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.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-1402, USA.
Alessandra
A
Ferrajoli
Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Cristina
C
Ivan
Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-1402, USA ; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Maria
M
Ciccone
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Masayoshi
M
Shimizu
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Yoshiaki
Y
Kita
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Masahisha
M
Ohtsuka
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA ; Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, 44100, Via Fossato di Mortara, 70, Italy.
Lucilla
L
D'Abundo
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA ; Department of Microbiology, Harbin Medical University, 150081 Harbin, China.
Jun
J
Qiang
Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-1402, USA.
Susan
S
Lerner
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Nazila
N
Nouraee
Department of Health Science Research, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA.
Kari G
KG
Rabe
University of California San Diego, Moores Cancer Center, La Jolla, 3855 Health Sciences Dr, Rm 4307, San Diego, CA 92093-0820, USA.
Laura Z
LZ
Rassenti
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Katrien
K
Van Roosbroeck
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
John T
JT
Manning
Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA ; Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX, USA.
Yuan
Y
Yuan
Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Xinna
X
Zhang
Department of Internal Medicine, Division of Hematology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA.
Tait D
TD
Shanafelt
Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-1402, USA.
William G
WG
Wierda
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, 44100, Via Fossato di Mortara, 70, Italy.
Silvia
S
Sabbioni
Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Jeffrey J
JJ
Tarrand
Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-1402, USA.
Zeev
Z
Estrov
Department of Surgery, Division of General Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Emerson Hall 203, IN, 46202 USA ; Department of Medical and Molecular Genetics, Indiana University School of Medicine, 545 Barnhill Drive, Emerson Hall 203, IN, 46202 USA.
Milan
M
Radovich
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX, USA.
Han
H
Liang
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, 44100, Via Fossato di Mortara, 70, Italy.
Massimo
M
Negrini
University of California San Diego, Moores Cancer Center, La Jolla, 3855 Health Sciences Dr, Rm 4307, San Diego, CA 92093-0820, USA.
Thomas J
TJ
Kipps
Department of Internal Medicine, Division of Hematology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA.
Neil E
NE
Kay
Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-1402, USA.
Michael
M
Keating
Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-1402, USA ; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA ; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
George A
GA
Calin
D018572:Disease-Free Survival; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000401:mortality / Q000821:virology*; D035683:MicroRNAs / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53; D014763:Viral Matrix Proteins / Q000235:genetics; D014764:Viral Proteins / Q000097:blood / Q000235:genetics*; D001613:beta 2-Microglobulin / Q000097:blood
C083278:BHRF1 protein, Human herpesvirus 4; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; C099537:Epstein-Barr virus encoded RNA 1; D035683:MicroRNAs; D012367:RNA, Viral; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014763:Viral Matrix Proteins; D014764:Viral Proteins; D001613:beta 2-Microglobulin; C417029:EBV-encoded nuclear antigen 1
BHRF1-1; Chronic lymphocytic leukemia; Epstein–Barr Virus; Overall survival; miRNAs