High Viral Loads of Epstein-Barr Virus DNA in Peripheral Blood of Patients with Chronic Lymphocytic Leukemia Associated with Unfavorable Prognosis.

Ewelina Grywalska,Agnieszka Grafka,Jacek Roliński,Elżbieta Starosławska,Piotr Grabarczyk,Maciej Maj,Anna Malm,Stanisław Góźdź,Marcin Pasiarski,Izabela Korona-Glowniak,Agata Surdacka,Agnieszka Stelmach-Gołdyś,Michał Zgurski,Joseph S Pagano

doi:10.1371/journal.pone.0140178

Abstract

Epstein-Barr virus (EBV) is a ubiquitous γ-herpesvirus that infects more than 90% of the world population. The potential involvement of EBV in the clinical course of chronic lymphocytic leukemia (CLL) remains unexplained. The aim of this study was to determine whether EBV-DNA load in the peripheral blood mononuclear cells (PBMCs) of CLL patients may influence heterogeneity in the course of the disease. The study included peripheral blood samples from 115 previously untreated patients with CLL (54 women and 61 men) and 40 healthy controls (16 women and 24 men). We analyzed the association between the EBV-DNA load in PBMCs and the stage of the disease, adverse prognostic factors, and clinical outcome. Detectable numbers of EBV-DNA copies in PBMCs were found in 62 out of 115 CLL patients (53.91%). The EBV-DNA copy number/μg DNA was significantly higher in patients who required early implementation of treatment, presented with lymphocyte count doubling time <12 months, displayed CD38-positive or ZAP-70-positive phenotype, and with the del(11q22.3) cytogenetic abnormality. Furthermore, the EBV-DNA copy number/μg DNA showed significant positive correlation with the concentrations of lactate dehydrogenase (LDH) and beta-2-microglobulin. We have shown that in CLL patients, higher EBV-DNA copy number predicted shorter survival and shorter time to disease progression, and it was associated with other established unfavorable prognostic factors. This suggests that EBV may negatively affect the outcome of CLL.

Highlights

Epstein-Barr virus (EBV), referred to as human herpesvirus 4 (HHV-4), is the first identified human virus with documented involvement in carcinogenesis [1]
The peripheral blood mononuclear cells (PBMCs) of 115 chronic lymphocytic leukemia (CLL) patients and 40 controls were tested for the presence of EBV-DNA with an aid of real-time PCR
The following three groups were identified on the basis of this criterion: (a) CLL patients whose PBMCs showed the presence of the EBV-DNA, i.e. the EBV(+) group, (b) CLL patients whose PBMCs lacked the EBV-DNA, i.e. the EBV(–) group and (c) healthy controls

Summary

Introduction

Epstein-Barr virus (EBV), referred to as human herpesvirus 4 (HHV-4), is the first identified human virus with documented involvement in carcinogenesis [1]. Many cells of the nonHodgkin lymphomas (NHL) show the presence of the monoclonal form of EBV genome (i.e. the EBV-positive phenotype). This finding points to the origin of the malignancy from a single infected cell and involvement of EBV in its pathogenesis [2, 3]. 30% of patients survive up to 10–20 years after diagnosis [7]. The individuals with the aggressive form of CLL survive no more than 2–3 years after diagnosis [8]. The reasons for such heterogeneous natural history of the condition remain unclear

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