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Viruses 2017, 9(7), 164; doi:10.3390/v9070164

LMP1 and Dynamic Progressive Telomere Dysfunction: A Major Culprit in EBV-Associated Hodgkin’s Lymphoma

1
Division of Haematology, Department of Medicine, Jewish General Hospital, McGill University, Montréal, QC H3T 1E2, Canada
2
Manitoba Institute of Cell Biology, The Genomic Centre for Cancer Research and Diagnosis, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
*
Author to whom correspondence should be addressed.
Academic Editors: Paul M. Lieberman and Benedikt B. Kaufer
Received: 15 May 2017 / Revised: 12 June 2017 / Accepted: 22 June 2017 / Published: 27 June 2017
(This article belongs to the Special Issue Viruses and Telomeres)
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Abstract

Epstein–Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is expressed in germinal-center-derived, mononuclear Hodgkin (H) and multinuclear, diagnostic Reed–Sternberg (RS) cells in classical EBV-positive Hodgkin’s lymphoma (cHL). LMP1 expression in EBV-negative H-cell lines results in a significantly increased number of RS cells. In a conditional, germinal-center-derived B-cell in vitro system, LMP1 reversibly down-regulates the shelterin proteins, telomeric repeat binding factor (TRF)1, TRF2, and protection of telomeres (POT)1. This down-regulation is associated with progressive 3D shelterin disruption, resulting in telomere dysfunction, progression of complex chromosomal rearrangements, and multinuclearity. TRF2 appears to be the key player. Thus, we hypothesize that the 3D interaction of telomeres and TRF2 is disrupted in H cells, and directly associated with the formation of H and RS cells. Using quantitative 3D co-immuno-TRF2-telomere fluorescent in situ hybridization (3D TRF2/Telo-Q-FISH) applied to monolayers of primary H and RS cells, we demonstrate TRF2-telomere dysfunction in EBV-positive cHL. However, in EBV-negative cHL a second molecular mechanism characterized by massive up-regulation of TRF2, but attrition of telomere signals, is also identified. These facts point towards a shelterin-related pathogenesis of cHL, where two molecularly disparate mechanisms converge at the level of 3D Telomere–TRF2 interactions, leading to the formation of RS cells. View Full-Text
Keywords: LMP1; EBV; TRF2; telomere; shelterin; Reed–Sternberg cell; Hodgkin’s lymphoma; 3D TRF2/Telo-Q-FISH LMP1; EBV; TRF2; telomere; shelterin; Reed–Sternberg cell; Hodgkin’s lymphoma; 3D TRF2/Telo-Q-FISH
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Knecht, H.; Mai, S. LMP1 and Dynamic Progressive Telomere Dysfunction: A Major Culprit in EBV-Associated Hodgkin’s Lymphoma. Viruses 2017, 9, 164.

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