Epstein-Barr virus latent membrane protein 2A exploits Notch1 to alter B-cell identity in vivo

Anderson, Leah J.; Longnecker, Richard

doi:10.1182/blood-2008-06-160937

Cited by 33 publications

(22 citation statements)

References 48 publications

(78 reference statements)

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“…1 To evaluate the possibility of EBV infection in those sporadic H/DC sarcomas that carried a B-cell genotype with clonal IGH/ IGK rearrangements, we examined the EBV status in 8 of the 11 cases of our series by in situ hybridization for EBER. No evidence of EBV infection was detected in the cases studied, suggesting that EBV may not play an important role in the pathogenesis of these particular H/DC sarcomas.…”

Section: Discussionmentioning

confidence: 99%

High Frequency of Clonal Immunoglobulin Receptor Gene Rearrangements in Sporadic Histiocytic/Dendritic Cell Sarcomas

Chen

Lau

Fong

et al. 2009

American Journal of Surgical Pathology

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The diagnosis of histiocytic/dendritic cell (H/DC) sarcomas is currently based on morphology and the presence of immunophenotypic features of H/DC differentiation. The issue whether clonal immunoglobulin receptor gene rearrangements are present in H/DC sarcomas has been debated over decades until the recent data by Feldman et al, which provided compelling evidence that patients with follicular lymphoma and concurrent/synchronous H/DC sarcoma share identical genotypic features, suggested the possibility of transdifferentiation or dedifferentiation of 2 otherwise morphologically and immunophenotypically distinctive neoplasms. Here we investigated the molecular characteristics of 23 patients with sporadic H/DC sarcoma. Nine of the 23 cases (39%) showed clonal IGH (+/-IGK) gene rearrangements, whereas 2 (9%) cases showed only clonal IGK gene rearrangements, which were further validated and confirmed by direct DNA sequencing. One histiocytic sarcoma showed t(14;18) by quantitative-polymerase chain reaction, which was confirmed by fluorescence in situ hybridization analysis showing IGH/BCL2 fusions in neoplastic histiocytes. Notably, all IGH/IGK-positive H/DC sarcomas were negative for B-cell-associated transcription factors PAX5 and BOB.1, whereas 4 of 7 IGH/IGK-positive histiocytic sarcoma cases were positive for Oct2. In addition, no evidence of Epstein-Barr virus infection was detected in 8 of 11 IGH/IGK-positive H/DC sarcoma cases by in situ hybridization, suggesting that Epstein-Barr virus infection may not play an important role in the pathogenesis of these tumors. This study provides evidence that clonal immunoglobulin receptor gene rearrangements may be detected at a high frequency in sporadic H/DC sarcomas. The findings suggest that a large subset of H/DC sarcomas have inherited B-cell genotypes, thus providing new insights for the pathogenesis of these rare but aggressive neoplasms.

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Section: Discussionmentioning

confidence: 99%

High Frequency of Clonal Immunoglobulin Receptor Gene Rearrangements in Sporadic Histiocytic/Dendritic Cell Sarcomas

Chen

Lau

Fong

et al. 2009

American Journal of Surgical Pathology

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“…Interestingly, some cases of PTLD lack CD20 expression, and it is hypothesized that downregulation of CD20 and other B cell markers occurs in response to EBV infection (8,170). An analogous process is thought to account for virusmediated reprogramming of the B cell phenotype in classical Hodgkin lymphomas (176).…”

Section: B Cell Lineage and Viral Reprogrammingmentioning

confidence: 99%

Using Epstein-Barr Viral Load Assays To Diagnose, Monitor, and Prevent Posttransplant Lymphoproliferative Disorder

2010

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SUMMARYEpstein-Barr virus (EBV) DNA measurement is being incorporated into routine medical practice to help diagnose, monitor, and predict posttransplant lymphoproliferative disorder (PTLD) in immunocompromised graft recipients. PTLD is an aggressive neoplasm that almost always harbors EBV DNA within the neoplastic lymphocytes, and it is often fatal if not recognized and treated promptly. Validated protocols, commercial reagents, and automated instruments facilitate implementation of EBV load assays by real-time PCR. When applied to either whole blood or plasma, EBV DNA levels reflect clinical status with respect to EBV-related neoplasia. While many healthy transplant recipients have low viral loads, high EBV loads are strongly associated with current or impending PTLD. Complementary laboratory assays as well as histopathologic examination of lesional tissue help in interpreting modest elevations in viral load. Circulating EBV levels in serial samples reflect changes in tumor burden and represent an effective, noninvasive tool for monitoring the efficacy of therapy. In high-risk patients, serial testing permits early clinical intervention to prevent progression toward frank PTLD. Restoring T cell immunity against EBV is a major strategy for overcoming PTLD, and novel EBV-directed therapies are being explored to thwart virus-driven neoplasia.

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“…Previously, it was reported that transgenic expression of the Epstein-Barr virus (EBV) LMP1 protein accelerated extrafollicular B-cell differentiation in vivo mimicking CD40 signaling (60), that EBV LMP2A enhances B-cell responses (4,56), and that murine herpesvirus 68 (MHV68) coinfection fosters macrophage responses to bacterial antigens (7). The present study is the first demonstration that B cells expressing a KSHV viral protein displayed enhanced response to a T-dependent antigen.…”

mentioning

confidence: 67%

“…EBV latent genes also confer a proliferative advantage upon B cells in transgenic mice, and LMP2A enhances B-cell responses in vivo (4,52,56,60). This reflects the evolutionary conservation of B-cell signaling and its importance in gammaherpesvirus latency.…”

Section: Discussionmentioning

confidence: 98%

The Viral Latency-Associated Nuclear Antigen Augments the B-Cell Response to AntigenIn Vivo

Sin

Fakhari

Dittmer

2010

J Virol

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Gammaherpesviruses, including Kaposi sarcoma-associated herpesvirus (KSHV), establish latency in B cells. We hypothesized that the KSHV latency-associated nuclear antigen (LANA/orf73) provides a selective advantage to infected B cells by driving proliferation in response to antigen. To test this, we used LANA B-cell transgenic mice. Eight days after immunization with antigen without adjuvant, LANA mice had significantly more activated germinal center (GC) B cells (CD19 ؉ PNA ؉ CD71 ؉ ) than controls. This was dependent upon B-cell receptor since LANA did not restore the GC defect of CD19 knockout mice. However, LANA was able to restore the marginal zone defect in CD19 knockout mice.

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Epstein-Barr virus latent membrane protein 2A exploits Notch1 to alter B-cell identity in vivo

Cited by 33 publications

References 48 publications

High Frequency of Clonal Immunoglobulin Receptor Gene Rearrangements in Sporadic Histiocytic/Dendritic Cell Sarcomas

High Frequency of Clonal Immunoglobulin Receptor Gene Rearrangements in Sporadic Histiocytic/Dendritic Cell Sarcomas

Using Epstein-Barr Viral Load Assays To Diagnose, Monitor, and Prevent Posttransplant Lymphoproliferative Disorder

The Viral Latency-Associated Nuclear Antigen Augments the B-Cell Response to AntigenIn Vivo

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