EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors
Robert E. White, … , Christian Münz, Martin J. Allday
Robert E. White, … , Christian Münz, Martin J. Allday
Published March 12, 2012
Citation Information: J Clin Invest. 2012;122(4):1487-1502. https://doi.org/10.1172/JCI58092.
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Research Article Oncology

EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors

Abstract

Epstein-Barr virus (EBV) persistently infects more than 90% of the human population and is etiologically linked to several B cell malignancies, including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and diffuse large B cell lymphoma (DLBCL). Despite its growth transforming properties, most immune-competent individuals control EBV infection throughout their lives. EBV encodes various oncogenes, and of the 6 latency-associated EBV-encoded nuclear antigens, only EBNA3B is completely dispensable for B cell transformation in vitro. Here, we report that infection with EBV lacking EBNA3B leads to aggressive, immune-evading monomorphic DLBCL-like tumors in NOD/SCID/γc–/– mice with reconstituted human immune system components. Infection with EBNA3B-knockout EBV (EBNA3BKO) induced expansion of EBV-specific T cells that failed to infiltrate the tumors. EBNA3BKO-infected B cells expanded more rapidly and secreted less T cell–chemoattractant CXCL10, reducing T cell recruitment in vitro and T cell–mediated killing in vivo. B cell lines from 2 EBV-positive human lymphomas encoding truncated EBNA3B exhibited gene expression profiles and phenotypic characteristics similar to those of tumor-derived lines from the humanized mice, including reduced CXCL10 secretion. Screening EBV-positive DLBCL, HL, and BL human samples identified additional EBNA3B mutations. Thus, EBNA3B is a virus-encoded tumor suppressor whose inactivation promotes immune evasion and virus-driven lymphomagenesis.

Authors

Robert E. White, Patrick C. Rämer, Kikkeri N. Naresh, Sonja Meixlsperger, Laurie Pinaud, Cliona Rooney, Barbara Savoldo, Rita Coutinho, Csaba Bödör, John Gribben, Hazem A. Ibrahim, Mark Bower, Jamie P. Nourse, Maher K. Gandhi, Jaap Middeldorp, Fathima Z. Cader, Paul Murray, Christian Münz, Martin J. Allday

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Figure 1

EBNA3BKO infection of mice with reconstituted human immune system components leads to splenomegaly and tumor formation.

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EBNA3BKO infection of mice with reconstituted human immune system compon...
(A) Reconstitution levels of human lymphocytes in mice used to study in vivo biology of EBNA3BKO (n = 66). Frequencies of human lymphocytes in peripheral blood of mice were determined by flow cytometry. Reconstitution levels for each animal are provided in Supplemental Table 1. (B) Macroscopically visible tumors (arrows) in spleens of animals 28 days after infection with PBS, wtBAC, EBNA3Brev, or EBNA3BKO by i.p. injection. Scale bars: 1 cm. (C) Frequency of overt tumor formation 28 days after infection. (D) Spleen/body weight ratio 28 days after infection. Data points represent individual mice; horizontal bars represent means. Shown is 1 representative of 3 experiments (B and D) or pooled data from 3 experiments (C).