Frequent downregulation of BTB and CNC homology 2 expression in Epstein-Barr virus-positive diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell lymphoma subtype, and the Epstein-Barr virus (EBV)-positive subtype of DLBCL is known to show a more aggressive clinical behavior than the EBV-negative one. BTB and CNC homology 2 (BACH2) has been highlighted as a tumor suppressor in hematopoietic malignancies; however, the role of BACH2 in EBV-positive DLBCL is unclear. In the present study, BACH2 expression and its significance were studied in 23 EBV-positive and 43 EBV-negative patient samples. Immunohistochemistry revealed BACH2 downregulation in EBV-positive cases (P < 0.0001), although biallelic deletion of BACH2 was not detected by FISH. Next, we analyzed the contribution of BACH2 negativity to aggressiveness in EBV-positive B-cell lymphomas using FL-18 (EBV-negative) and FL-18-EB cells (FL-18 sister cell line, EBV-positive). In BACH2-transfected FL-18-EB cells, downregulation of phosphorylated transforming growth factor-β-activated kinase 1 (pTAK1) and suppression in p65 nuclear fractions were observed by Western blot analysis contrary to non-transfected FL-18-EB cells. In patient samples, pTAK1 expression and significant nuclear p65, p50, and p52 localization were detected immunohistochemically in BACH2-negative DLBCL (P < 0.0001, P = 0.006, and P = 0.001, respectively), suggesting that BACH2 downregulation contributes to constitutive activation of the nuclear factor-κB pathway through TAK1 phosphorylation in BACH2-negative DLBCL (most EBV-positive cases). Although further molecular and pathological studies are warranted to clarify the detailed mechanisms, downregulation of BACH2 may contribute to constitutive activation of the nuclear factor-κB pathway through TAK1 activation.

Noujima-Harada M ，Takata K ，Miyata-Takata T ，Sakurai H ，Igarashi K ，Ito E ，Nagakita K ，Taniguchi K ，Ohnishi N ，Omote S ，Tabata T ，Sato Y ，Yoshino T ... -  《-》

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

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.

Kato H ，Karube K ，Yamamoto K ，Takizawa J ，Tsuzuki S ，Yatabe Y ，Kanda T ，Katayama M ，Ozawa Y ，Ishitsuka K ，Okamoto M ，Kinoshita T ，Ohshima K ，Nakamura S ，Morishima Y ，Seto M ... -  《-》

pSTAT3 and MYC in Epstein-Barr virus-positive diffuse large B-cell lymphoma.

Teoh SH ，Khoo JJ ，Abdul Salam DSD ，Peh SC ，Cheah SC ... -  《Malaysian Journal of Pathology》

Expression of co-inhibitory molecules B7-H4 and B7-H1 in Epstein-Barr virus positive diffuse large B-cell lymphoma and their roles in tumor invasion.

To investigate the relationship between immunoregulatory molecules B7-H4 and B7-H1 in Epstein-Barr positive diffuse large B-cell lymphoma (EBV+DLBCL). Immunohistochemistry was used to detect the expression of B7-H4 and B7-H1 in tumor tissues of 13 patients with EBV+DLBCL. The expression levels of B7-H4 and B7-H1 in four diffuse large B-cell lymphoma cell lines (SU-DHL-4, SU-DHL-10, SU-DHL-6, Pfeiffer) were analyzed by flow cytometry. Transwell invasion assays were conducted to observe the invasive ability of cell lines. B7-H4 and B7-H1 were expressed in 84.62% and 100% tumor specimens of EBV+DLBCL. The overexpression of B7-H4 and B7-H1 was found in 46.15% and 23.08% tumor samples of EBV+DLBCL. There was a medium negative correlation between the expression levels of B7-H4 and B7-H1 (r = -0.667, P = 0.013, spearman rank correlation). The expression levels of B7-H1 in four diffuse large B-cell lymphoma cell lines were positively correlated with their invasive ability, whereas the expression levels of B7-H4 were not. Here, we provide evidence for the negative relationship between B7-H4 and B7-H1 in EBV+DLBCL. The expression of B7-H1 in EBV+DLBCL appears to be the dominant factor which affects tumor aggressiveness. When B7-H1 expression weakens, the molecule B7-H4 may become the dominant factor of prognosis in patients with EBV+DLBCL.

Jiang Y ，Lin J ，Zhang J ，Lu S ，Wang C ，Tong Y ... -  《-》

A20 (TNFAIP3) deletion in Epstein-Barr virus-associated lymphoproliferative disorders/lymphomas.

Ando M ，Sato Y ，Takata K ，Nomoto J ，Nakamura S ，Ohshima K ，Takeuchi T ，Orita Y ，Kobayashi Y ，Yoshino T ... -  《PLoS One》