Comparative analysis of oncogenic properties and nuclear factor- B activity of latent membrane protein 1 natural variants from Hodgkin's lymphoma's Reed-Sternberg cells and normal B-lymphocytes

Faumont, Nathalie; Chanut, Aurélie; Bénard, Alan; Cogné, Nadine; Delsol, Georges; Feuillard, Jean

doi:10.3324/haematol.13269

Cited by 9 publications

(12 citation statements)

References 41 publications

(56 reference statements)

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“…EBNA1 promotes telomere dysfunction via induction of oxidative stress [25], and through tethering of TRF1 associated tankyrase [26]. Moreover, H-cells and RS-cells harbour LMP1 variants with higher oncogenic potential [27] and very high NF-κB activation potential [28]. There is accumulating evidence that in EBV-associated HL this virus acts as a double cutting sword.…”

Section: Ebv Is Probably Not An Innocent Bystandermentioning

confidence: 99%

Genomic Instability: The Driving Force behind Refractory/Relapsing Hodgkin’s Lymphoma

Knecht

Righolt

Mai

2013

Cancers

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In classical Hodgkin’s lymphoma (HL) the malignant mononuclear Hodgkin (H) and multinuclear, diagnostic Reed-Sternberg (RS) cells are rare and generally make up <3% of the total cellular mass of the affected lymph nodes. During recent years, the introduction of laser micro-dissection techniques at the single cell level has substantially improved our understanding of the molecular pathogenesis of HL. Gene expression profiling, comparative genomic hybridization analysis, micro-RNA expression profiling and viral oncogene sequencing have deepened our knowledge of numerous facets of H- and RS-cell gene expression deregulation. The question remains whether disturbed signaling pathways and deregulated transcription factors are at the origin of refractory/relapsing Hodgkin’s lymphoma or whether these hallmarks are at least partially related to another major factor. We recently showed that the 3D nuclear organization of telomeres and chromosomes marked the transition from H- to RS-cells in HL cell lines. This transition is associated with progression of telomere dysfunction, shelterin disruption and progression of complex chromosomal rearrangements. We reported analogous findings in refractory/relapsing HL and identified the shelterin proteins TRF1, TRF2 and POT1 as targets of the LMP1 oncogene in post-germinal center B-cells. Here we summarize our findings, including data not previously published, and propose a model in which progressive disruption of nuclear integrity, a form of genomic instability, is the key-player in refractory/relapsing HL. Therapeutic approaches should take these findings into account.

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Section: Ebv Is Probably Not An Innocent Bystandermentioning

confidence: 99%

Genomic Instability: The Driving Force behind Refractory/Relapsing Hodgkin’s Lymphoma

Knecht

Righolt

Mai

2013

Cancers

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“…Since whole-genome sequencing requires relatively large volumes of blood (especially during chronic infection, when circulating memory B cell frequencies are low), we targeted LMP1 for amplification and sequencing. LMP1 is an integral transmembrane protein with relatively high genetic diversity, functional importance, and a large number of known CD8 ϩ T cell epitopes (33)(34)(35)(36)(37)(38)(39). It consists of a short amino-terminal cytoplasmic tail (amino acids [aa] 1 to 25), six transmembrane domains (aa 26 to 196), and a carboxyl-terminal tail (aa 197 to 386).…”

Section: Importancementioning

confidence: 99%

Epstein-Barr Virus Latent Membrane Protein 1 Genetic Variability in Peripheral Blood B Cells and Oropharyngeal Fluids

Renzette

Somasundaran

Brewster

et al. 2014

J Virol

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We report the diversity of latent membrane protein 1 (LMP1) gene founder sequences and the level of Epstein-Barr virus (EBV) genome variability over time and across anatomic compartments by using virus genomes amplified directly from oropharyngeal wash specimens and peripheral blood B cells during acute infection and convalescence. The intrahost nucleotide variability of the founder virus was 0.02% across the region sequences, and diversity increased significantly over time in the oropharyngeal compartment (P ‫؍‬ 0.004). The LMP1 region showing the greatest level of variability in both compartments, and over time, was concentrated within the functional carboxyl-terminal activating regions 2 and 3 (CTAR2 and CTAR3). Interestingly, a deletion in a proline-rich repeat region (amino acids 274 to 289) of EBV commonly reported in EBV sequenced from cancer specimens was not observed in acute infectious mononucleosis (AIM) patients. Taken together, these data highlight the diversity in circulating EBV genomes and its potential importance in disease pathogenesis and vaccine design. IMPORTANCEThis study is among the first to leverage an improved high-throughput deep-sequencing methodology to investigate directly from patient samples the degree of diversity in Epstein-Barr virus (EBV) populations and the extent to which viral genome diversity develops over time in the infected host. Significant variability of circulating EBV latent membrane protein 1 (LMP1) gene sequences was observed between cellular and oral wash samples, and this variability increased over time in oral wash samples. The significance of EBV genetic diversity in transmission and disease pathogenesis are discussed.

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“…Furthermore, it is important to note that, among the different NF-κB subunits, c-Rel is specifically activated in lymphomas occurring in LMP1 transgenic mice (46). Even in the presence of mutations or deletions occurring within NF-κB activation domains, LMP1 natural variants from EBV still have the capacity to activate NF-κB, possibly resulting from a selection pressure (20,22). Our results show that LMP1 natural variants from Hodgkin's lymphomas also conserve the capacity to activate Polβ expression.…”

Section: Discussionmentioning

confidence: 99%

“…The LMP1 coding sequences from B95.8 LCL and two Hodgkin's lymphoma infiltrated lymph nodes (HL1 and HL2) were amplified and inserted into pCR 3.1-Uni vector (Invitrogen) as previously described (18)(19)(20). The pRT-1 doxycyclin double inducible episomal vector for truncated NGFR (NGFR-t) and a cDNA of interest is described elsewhere (21,22).…”

Section: Methodsmentioning

confidence: 99%

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Regulation of DNA Polymerase β by the LMP1 Oncoprotein of EBV through the Nuclear Factor-κB Pathway

et al. 2009

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The repair DNA polymerase β (Polβ), when overexpressed, plays a critical role in generating genetic instability via its interference with the genomic replication program. Up-regulation of Polβ has been reported in many tumor types that exhibit genetic aberrations, including EBV-related B-cell lymphomas. However, the mechanisms responsible for its overexpression have never been examined. Here, we report that both expression and activity of Polβ, in EBV-immortalized B cells, are induced by several natural genetic variants of LMP1, an oncoprotein associated with the vast majority of EBV-related tumors. Conversely, we found that the expression of Polβ decreased when LMP1 signaling was down-regulated by a dominant negative of LMP1 or an inhibitor of the nuclear factor-κB (NF-κB) pathway, the main transduction pathway activated by LMP1, strongly supporting a role of NF-κB in the LMP1-mediated Polβ regulation. Using electrophoretic mobility shift assay experiments from several EBV-immortalized B-cell nuclear extracts, we identified an LMP1-dependent p50/c-Rel heterodimer on a proximal κB binding site (−211 to −199nt) of the Polβ promoter. This result was correlated with a specific Polβ κB transcriptional activity. Taken together, our data enlighten a new mechanism responsible for Polβ overexpression in EBV-infected cells, mediated by LMP1 and dependent on NF-κB activation. [Cancer Res 2009; 69(12):5177-85]

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Comparative analysis of oncogenic properties and nuclear factor- B activity of latent membrane protein 1 natural variants from Hodgkin's lymphoma's Reed-Sternberg cells and normal B-lymphocytes

Cited by 9 publications

References 41 publications

Genomic Instability: The Driving Force behind Refractory/Relapsing Hodgkin’s Lymphoma

Genomic Instability: The Driving Force behind Refractory/Relapsing Hodgkin’s Lymphoma

Epstein-Barr Virus Latent Membrane Protein 1 Genetic Variability in Peripheral Blood B Cells and Oropharyngeal Fluids

Regulation of DNA Polymerase β by the LMP1 Oncoprotein of EBV through the Nuclear Factor-κB Pathway

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