Epstein‐Barr virus (EBV)‐associated antibody patterns in malignant lymphoma and leukemia. I. Hodgkin's disease

Johansson, Bo; Klein, George; Henle, Werner; Henle, Gertrude

doi:10.1002/ijc.2910060316

Cited by 175 publications

(61 citation statements)

References 20 publications

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“…EBV has also been linked with HL by other lines of evidence. Serologically, HL patients seem to have elevated anti-EBV antibody titers both before (19) and at (20) HL diagnosis, and more compellingly, clonal EBV genome products can be shown in the neoplastic Hodgkin-Reed-Sternberg (HRS) cells in the lymphoma (21).…”

Section: Introductionmentioning

confidence: 99%

Infectious Mononucleosis, Childhood Social Environment, and Risk of Hodgkin Lymphoma

Smedby²,

et al. 2007

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Infectious mononucleosis (IM) has been associated with an increased risk of Hodgkin lymphoma (HL), implicating a role for Epstein-Barr virus (EBV) in HL development. Although essential to the understanding of the association, it has remained uncertain if the relationship is restricted to the EBVpositive subset of HL. We collected information on mononucleosis history and childhood socioenvironmental characteristics in a population-based study of 586 patients with classic HL and 3,187 controls in Denmark and Sweden. Tumor EBV status was established for 499 cases by immunohistochemistry and in situ hybridization techniques. Odds ratios (OR) for the relationship between HL risk and mononucleosis and other risk factors were estimated by logistic regression for HL in younger (18-44 years) and older (45-74 years) adults, overall and by tumor EBV status. All analyses were adjusted for country-specific measures of maternal education and mononucleosis history. IM was associated with an increased risk of EBV-positive [OR, 3.23; 95% confidence interval (95% CI) 1.89-5.55] but not EBV-negative HL (OR, 1.35; 95% CI, 0.86-2.14). Risk of EBV-positive HL varied with time since IM and was particularly pronounced in younger adults (OR, 3.96; 95% CI,). IM-associated lymphomas occurred with a median of 2.9 years (1.8-4.9 years) after infection. The EBV specificity of the IM association was corroborated by a casecase comparison of IM history between younger adult EBVpositive and EBV-negative HL patients (OR IM EBV+ HL versus EBVÀ HL , 2.68; 95% CI, 1.40-5.12). We found further evidence that IM is associated only with EBV-positive HL. This finding is compatible with the notion that EBV-positive and EBV-negative HL may have different etiologies. [Cancer Res 2007;67(5):2382-8]

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Section: Introductionmentioning

confidence: 99%

Infectious Mononucleosis, Childhood Social Environment, and Risk of Hodgkin Lymphoma

Smedby²,

et al. 2007

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“…EBV is also an important cause of endemic Burkitt Lymphoma (1), Hodgkin Lymphoma (2), and lymphoproliferative disorders in immune-suppressed (3) and HIV-infected people (4). In early primary human infection, EBV infects peripheral resting B lymphocytes (RBLs) and expresses six nuclear (Epstein-Barr virus nuclear antigen, EBNA) and two integral membrane (LMP) proteins.…”

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confidence: 99%

Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth

Zhao¹,

Zou

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

185

267

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Epstein-Barr virus nuclear antigen 2 (EBNA2) regulation of transcription through the cell transcription factor RBPJ is essential for resting B-lymphocyte (RBL) conversion to immortal lymphoblast cell lines (LCLs). ChIP-seq of EBNA2 and RBPJ sites in LCL DNA found EBNA2 at 5,151 and RBPJ at 10,529 sites. EBNA2 sites were enriched for RBPJ (78%), early B-cell factor (EBF, 39%), RUNX (43%), ETS (39%), NFκB (22%), and PU.1 (22%) motifs. These motif associations were confirmed by LCL RBPJ ChIP-seq finding 72% RBPJ occupancy and Encyclopedia Of DNA Elements LCL ChIP-seq finding EBF, NFκB RELA, and PU.1 at 54%, 31%, and 17% of EBNA2 sites. EBNA2 and RBPJ were predominantly at intergene and intron sites and only 14% at promoter sites. K-means clustering of EBNA2 site transcription factors identified RELA-ETS, EBF-RUNX, EBF, ETS, RBPJ, and repressive RUNX clusters, which ranked from highest to lowest in H3K4me1 signals and nucleosome depletion, indicative of active chromatin. Surprisingly, although quantitatively less, the same genome sites in RBLs exhibited similar high-level H3K4me1 signals and nucleosome depletion. The EBV genome also had an LMP1 promoter EBF site, which proved critical for EBNA2 activation. LCL HiC data mapped intergenic EBNA2 sites to EBNA2 upregulated genes. FISH and chromatin conformation capture linked EBNA2/RBPJ enhancers 428 kb 5′ of MYC to MYC. These data indicate that EBNA2 evolved to target RBL H3K4me1 modified, nucleosome-depleted, nonpromoter sites to drive B-lymphocyte proliferation in primary human infection. The primed RBL program likely supports antigen-induced proliferation.pstein Barr virus (EBV) infection is highly prevalent in all human populations. EBV is also an important cause of endemic Burkitt Lymphoma (1), Hodgkin Lymphoma (2), and lymphoproliferative disorders in immune-suppressed (3) and HIV-infected people (4). In early primary human infection, EBV infects peripheral resting B lymphocytes (RBLs) and expresses six nuclear (Epstein-Barr virus nuclear antigen, EBNA) and two integral membrane (LMP) proteins. EBNAs and LMPs convert RBLs into proliferating lymphoblastoid cells (LCLs), which are malignant in the absence of effective T-cell responses. Because EBNAs and LMPs include >4,000 amino acids, T-cell immune responses normally eliminate most EBV-infected cells. Lymphocytes with down-regulated EBV protein expression persist in tonsils and lymph nodes and are reservoirs for reactivated EBV infection (4). EBV conversion of RBLs into LCLs in vitro (5) is a relevant and experimentally useful model for EBV proliferative effects in B-lymphocytes.In converting RBLs to LCLs, EBNA2 and EBNALP are expressed first. EBNA2 up-regulates EBV and cell gene expression, including EBV LMP1 and cell MYC, CD23, and CD21 (6-9). EBNA2 associates with DNA through RBPJ, which also mediates Notch binding to DNA (10, 11). The B-lymphocyte and macrophage lineage ETS protein, PU.1, is also important in EBNA2 activation of the EBV LMP1 promoter (12, 13). The EBNA2 C-terminal acidic domain recruits basal ...

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“…Although EBV infection is commonly asymptomatic, infection by this virus also causes infectious mononucleosis (Diehl et al, 1968) and is closely associated with many neoplastic disorders (Einhorn et al, 1970;Gunven et al, 1970;Johansson et al, 1970;Klein et al, 1970). Although EBV typically remains latent after infection of B lymphocytes, the virus must enter a lytic cycle to produce virus particles.…”

Section: Introductionmentioning

confidence: 99%

Activation of the ERK signal transduction pathway by Epstein–Barr virus immediate-early protein Rta

Lee¹,

Chiu

Wang

et al. 2008

Journal of General Virology

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BRCA1-associated protein 2 (BRAP2) is known to interact with the kinase suppressor of Ras 1 (KSR1), inhibiting the ERK signal transduction cascade. This study found that an Epstein-Barr virus (EBV) immediate-early protein, Rta, is a binding partner of BRAP2 in yeast and confirmed the binding in vitro by a glutathione S-transferase pull-down assay and in vivo by coimmunoprecipitation in 293(maxi-EBV) cells. Binding studies also showed that Rta and KSR1 interacted with the C-terminal 202 aa region in BRAP2. Additionally, Rta appeared to prevent the binding of KSR1 to BRAP2, activating the ERK signal transduction pathway and the transcription of an EBV immediate-early gene, BZLF1. Activation of the ERK signal transduction pathway by Rta may be critical for the maintenance of the lytic state of EBV. INTRODUCTIONEpstein-Barr virus (EBV) is a human herpesvirus that infects lymphoid and epithelial cells. Although EBV infection is commonly asymptomatic, infection by this virus also causes infectious mononucleosis (Diehl et al., 1968) and is closely associated with many neoplastic disorders (Einhorn et al., 1970;Gunven et al., 1970;Johansson et al., 1970;Klein et al., 1970). Although EBV typically remains latent after infection of B lymphocytes, the virus must enter a lytic cycle to produce virus particles. During the onset of the lytic cycle, the virus expresses the proteins Rta and Zta, encoded by BRLF1 and BZLF1, respectively, to activate the genes required for the viral lytic cycle (Chevallier-Greco et al., 1986;Chiu et al., 2007;Feederle et al., 2000;Granato et al., 2006;Hardwick et al., 1988;Lu et al., 2006). Although the exact means by which the EBV lytic cycle is activated in vivo is unknown, activation in vitro occurs after latently infected cells are exposed to 12-Otetradecanoylphorbol-13-acetate (TPA), calcium ionophores, transforming growth factor (TGF)-b1 or anti-IgG (Daibata et al., 1990; Faggioni et al., 1986;zur Hausen et al., 1978). TPA, anti-IgG and TGF-b1 are known to activate the ERK signal transduction pathway (Fahmi et al., 2000;Fenton & Sinclair, 1999;Gao et al., 2001;Satoh et al., 1999), which ultimately activates transcription of BZLF1 and the EBV lytic cycle (Borras et al., 1996;Flemington & Speck, 1990).It is known that EBV must express Zta to activate its lytic genes (Chevallier-Greco et al., 1986;Chiu et al., 2007;Feederle et al., 2000). Earlier studies have established that Rta upregulates transcription of the Zta gene, BZLF1 (Adamson et al., 2000;Ragoczy et al., 1998;Zalani et al., 1996). This activation is associated with activation of the p38 and JNK signal transduction pathway, causing the phosphorylation of ATF1/2 and the activation of transcription through an ATF1/ 2 site in the ZII region of the promoter (Adamson et al., 2000). However, the exact means by which Rta activates these signal transduction cascades is unknown. In this study, we used a yeast two-hybrid analysis to show that Rta interacts with BRCA1-associated protein 2 (BRAP2, also known as IMP), a protein that is known to i...

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Epstein‐Barr virus (EBV)‐associated antibody patterns in malignant lymphoma and leukemia. I. Hodgkin's disease

Abstract: Sera from Swedish patients with

Cited by 175 publications

References 20 publications

Infectious Mononucleosis, Childhood Social Environment, and Risk of Hodgkin Lymphoma

Infectious Mononucleosis, Childhood Social Environment, and Risk of Hodgkin Lymphoma

Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth

Activation of the ERK signal transduction pathway by Epstein–Barr virus immediate-early protein Rta

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