Gene expression profiling of Epstein–Barr virus‐positive diffuse large B‐cell lymphoma of the elderly reveals alterations of characteristic oncogenetic pathways

Abstract

Epstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly (EBV[+]DLBCL-E) is classified as a subtype of DLBCL. Until now, its molecular pathogenesis has remained unknown. To identify pathways characteristic of EBV(+)DLBCL-E, gene expression profiling of five EBV(+)DLBCL-E and seven EBV-negative DLBCL (EBV[−]DLBCL) cases was undertaken using human oligonucleotide microarray analysis. Gene set enrichment analysis and gene ontology analysis showed that gene sets of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and nuclear factor kappa B (NF-κB) pathways were enriched in EBV(+)DLBCL-E cases. To confirm the results of the expression profiles, in vitro analysis was performed. Expression profiling analysis showed that high activation of the JAK-STAT and NF-κB pathways was induced by EBV infection into DLBCL cell lines. Activation of the NF-κB pathway was confirmed in EBV-infected cell lines using an electrophoretic mobility shift assay. Western blot analysis revealed an increased protein expression level of phosphorylated signal transducer and activator of transcription 3 (STAT3) in an EBV-infected cell line. Protein expression of phosphorylated STAT3 was frequently observed in lymphoma cells of EBV(+)DLBCL-E clinical samples using immunohistochemistry (EBV[+]DLBCL-E: 80.0% [n = 20/25] versus EBV[−]DLBCL: 38.9% [n = 14/36]; P = 0.001). The results of the present study suggest that activation of the JAK-STAT and NF-κB pathways was characteristic of EBV(+)DLBCL-E, which may reflect the nature of EBV-positive tumor cells. Targeting these pathways as therapies might improve clinical outcomes of EBV(+)DLBCL-E.

The Role of EBV in the Pathogenesis of Diffuse Large B Cell Lymphoma

“…Over half of tumors demonstrated nuclear expression of both canonical and alternative NFκB pathways, significantly greater NFκB activity than that seen in ABC lymphoma alone. Furthermore, Kato et al (2014) found that infecting human ABC DLBCL-derived cell lines with EBV enhanced NFκB activity measured by electrophoretic mobility shift assay.…”

“…Age, by itself, is a risk for poorer outcomes in DLBCL. However, EBV-positive DLBCL is also associated with an ABC GEP, which is known to have a worse outcome than GCB tumors (Kato et al 2014;Ok et al 2014). Montes-Moreno et al (2012) explored whether the difference in survival was merely due to a higher prevalence of ABC phenotype.…”

“…There are additional biological differences that distinguish EBV-positive DLBCLs from other DLBCLs, particularly the activation of the NF-kB and JAK/STAT signaling pathways (Montes-Moreno et al 2012;Kato et al 2014).…”

EBV-positive large B-cell lymphomas in young patients: a nodal lymphoma with evidence for a tolerogenic immune environment

“…12-14 Most cases of DLBCL-E show activation of nuclear factor-kB pathway, 11,[15][16][17] most likely promoted by EBV through latent membrane protein 1 (LMP1) 18,19 and less likely by MYD88, CD79B, and CARD11 gene mutations. 20 Furthermore, gene expression profiling shows an enrichment of Janus kinasesignal transducer and activator of transcription-related genes (JAK/STAT), immune/inflammatory-related genes, and genes involved in cell-cycle progression and cellular metabolism.…”

“…20 Furthermore, gene expression profiling shows an enrichment of Janus kinasesignal transducer and activator of transcription-related genes (JAK/STAT), immune/inflammatory-related genes, and genes involved in cell-cycle progression and cellular metabolism. 15,16 Recent studies using high-resolution array comparative genomic hybridization reported cytogenetic abnormalities shared among DLBCL-E, plasmablastic lymphoma, posttransplant lymphoproliferative disorders and EBV-negative DLBCL-not otherwise specified (DLBCL-NOS). 20 Lack of uniform criteria (eg, age cutoff, percentage of EBV 1 tumor cells required for diagnosis, morphologic heterogeneity) may account for reported differences in disease prevalence and prognostic features.…”