Latent Epstein-Barr virus infection collaborates with Myc over-expression in normal human B cells to induce Burkitt-like Lymphomas in mice.

Autor: Bristol JA; Department of Oncology, McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin, United States of America., Nelson SE; Department of Oncology, McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin, United States of America., Ohashi M; Department of Oncology, McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin, United States of America., Casco A; Department of Oncology, McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin, United States of America., Hayes M; Department of Oncology, McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin, United States of America., Ranheim EA; Department of Pathology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America., Pawelski AS; Department of Oncology, McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin, United States of America., Singh DR; Department of Oncology, McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin, United States of America., Hodson DJ; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom., Johannsen EC; Department of Oncology, McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin, United States of America.; Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America., Kenney SC; Department of Oncology, McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin, United States of America.; Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2024 Apr 15; Vol. 20 (4), pp. e1012132. Date of Electronic Publication: 2024 Apr 15 (Print Publication: 2024).
DOI: 10.1371/journal.ppat.1012132
Abstrakt: Epstein-Barr virus (EBV) is an important cause of human lymphomas, including Burkitt lymphoma (BL). EBV+ BLs are driven by Myc translocation and have stringent forms of viral latency that do not express either of the two major EBV oncoproteins, EBNA2 (which mimics Notch signaling) and LMP1 (which activates NF-κB signaling). Suppression of Myc-induced apoptosis, often through mutation of the TP53 (p53) gene or inhibition of pro-apoptotic BCL2L11 (BIM) gene expression, is required for development of Myc-driven BLs. EBV+ BLs contain fewer cellular mutations in apoptotic pathways compared to EBV-negative BLs, suggesting that latent EBV infection inhibits Myc-induced apoptosis. Here we use an EBNA2-deleted EBV virus (ΔEBNA2 EBV) to create the first in vivo model for EBV+ BL-like lymphomas derived from primary human B cells. We show that cord blood B cells infected with both ΔEBNA2 EBV and a Myc-expressing vector proliferate indefinitely on a CD40L/IL21 expressing feeder layer in vitro and cause rapid onset EBV+ BL-like tumors in NSG mice. These LMP1/EBNA2-negative Myc-driven lymphomas have wild type p53 and very low BIM, and express numerous germinal center B cell proteins (including TCF3, BACH2, Myb, CD10, CCDN3, and GCSAM) in the absence of BCL6 expression. Myc-induced activation of Myb mediates expression of many of these BL-associated proteins. We demonstrate that Myc blocks LMP1 expression both by inhibiting expression of cellular factors (STAT3 and Src) that activate LMP1 transcription and by increasing expression of proteins (DNMT3B and UHRF1) known to enhance DNA methylation of the LMP1 promoters in human BLs. These results show that latent EBV infection collaborates with Myc over-expression to induce BL-like human B-cell lymphomas in mice. As NF-κB signaling retards the growth of EBV-negative BLs, Myc-mediated repression of LMP1 may be essential for latent EBV infection and Myc translocation to collaboratively induce human BLs.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Bristol et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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