title: LMP1 mediates multinuclearity through downregulation of shelterin proteins and formation of telomeric aggregates.
abstract: Hodgkin lymphoma (HL) and Burkitt lymphoma are both germinal center-derived B-cell lymphomas. To assess the consequences of permanent latent membrane protein 1 (LMP1) expression as observed in tumor cells of Epstein-Barr virus (EBV) -associated HL, we analyzed 3-dimensional (3D) telomere dynamics and measured the expression of shelterin proteins at the transcriptional and translational level and their topographic distribution in the EBV-negative Burkitt cell line BJAB stably transfected with an inducible LMP1 system. Stable LMP1 expression led to a highly significant increase of multinucleated cells, nuclear volume, and 3D telomeric aggregates when compared with the LMP1-suppressed BJAB controls. Most importantly, LMP1 induced a significant downregulation of the shelterin components TRF1, TRF2, and POT1 at the transcriptional and translational level, and this downregulation was reversed after resuppression of LMP1. In addition, as revealed by spectral karyotyping, LMP1 induced "outré" giant cells and hypoploid "ghost" cells. This LMP1-induced multinucleation was blocked upon LMP1-independent TRF2 expression. These results show that LMP1-dependent deregulation of telomere stability and nuclear organization via shelterin downregulation, in particular TRF2, favors chromosomal rearrangements. We speculate that telomeric aggregates and ongoing breakage-bridge-fusion cycles lead to disturbed cytokinesis and finally to multinuclearity, as observed in EBV-associated HL.
authors.affiliation: Divison d'Hématologie, Département de Médecine, Département de Microbiologie/Infectiologie, and.
authors.forename: Valérie
authors.initials: V
authors.lastname: Lajoie
authors.affiliation: Divison d'Hématologie, Département de Médecine, Département de Microbiologie/Infectiologie, and.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lemieux
authors.affiliation: Département de Pathologie, Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada;
authors.forename: Bassem
authors.initials: B
authors.lastname: Sawan
authors.affiliation: Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, MB, Canada; and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lichtensztejn
authors.affiliation: Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, MB, Canada; and.
authors.forename: Zelda
authors.initials: Z
authors.lastname: Lichtensztejn
authors.affiliation: Département de Microbiologie/Infectiologie, and.
authors.forename: Raymund
authors.initials: R
authors.lastname: Wellinger
authors.affiliation: Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, MB, Canada; and.
authors.forename: Sabine
authors.initials: S
authors.lastname: Mai
authors.affiliation: Divison d'Hématologie, Département de Médecine, Département de Microbiologie/Infectiologie, and Jewish General Hospital, McGill University, Montréal, QC, Canada.
authors.forename: Hans
authors.initials: H
authors.lastname: Knecht
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002472:Cell Transformation, Viral / Q000235:genetics; D015536:Down-Regulation; D015726:Giant Cells / Q000378:metabolism* / Q000473:pathology; D006689:Hodgkin Disease / Q000235:genetics / Q000473:pathology / Q000821:virology; D006801:Humans; D066329:Protein Aggregates / Q000235:genetics; D000089804:Shelterin Complex; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000502:physiology*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D066329:Protein Aggregates; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D014763:Viral Matrix Proteins