Association between Epstein-Barr virus LMP-1 and Hodgkin lymphoma LMP-1 mechanisms in Hodgkin lymphoma development.

Hodgkin lymphoma is histologically characterised by the presence of Hodgkin (H) and Reed-Sternberg (RS) cells originating from germinal centre B-cells rearranged in the IgV gene. The formation of multinucleated RS cells is a product of telomere organisation in a process initiated by telomere aggregate accumulation in mononuclear H cells and may be mediated by latent membrane protein 1 (LMP-1) expression. LMP-1 is the main oncoprotein of EBV and supports several tumourigenic processes. LMP-1 may rescue proapoptotic B-cells through downregulation of B-cell receptor (BCR) components, mimicking and inducing multiple distinct B-cell signalling pathways to promote proliferation and survival, such as Janus kinase-signal transducer and activator of transcription (JAK-STAT), nuclear factor-kappa b (NF-кB), and cellular MYC (c-MYC), and inducing telomere instability mainly through Telomere repeat binding factor 2 (TRF2) downregulation to promote the formation of multinucleated RS cells. This review presents recent discoveries regarding the influence of LMP-1 on the surviving cellular signalling, genomic instability and mecanical formation of HRS cells.

HHV8-positive, EBV-positive Hodgkin lymphoma-like large B cell lymphoma: expanding the spectrum of HHV8 and EBV-associated lymphoproliferative disorders.

Human herpesvirus type 8 (HHV8) is a gamma herpesvirus known for its role in lymphoid neoplasms, especially in immunosuppressed patients. We describe the case of a 64-year-old male, without known immunodeficiency, with 1-year-long clinical history of mediastinal and abdominal lymphadenopathies and recurrent pulmonary infections. Histopathological evaluation of a mediastinal lymph node revealed the presence of scattered atypical large cells with Hodgkin and Reed-Sternberg morphology in a background of lymphocytes and extensive areas of fibrosis. The large cells were positive for HHV8 and Epstein-Barr virus (EBV), with a clonal pattern of IGH gene rearrangement. A descriptive diagnosis of "HHV8-positive, EBV-positive Hodgkin lymphoma-like large B-cell lymphoma" was rendered. Interestingly, the retrospective evaluation of a previous biopsy, diagnosed as reactive lymphadenitis, revealed the presence of HHV8- and EBV-positive cells, with a polyclonal pattern and a small peak corresponding to that of the most recent biopsy. This case presents diagnostic challenges due to the presence of particular features not clearly related to current HHV8-associated entities, and also suggests the possibility for disease progression in the spectrum of HHV8- and EBV-associated lymphoproliferative disorders.

Chronic Active Epstein-Barr Virus Infection of T/NK-Cell Type Mimicking Classic Hodgkin Lymphoma: Clinicopathologic and Genetic Features of 8 Cases Supporting a Variant With "Hodgkin/Reed-Sternberg-like" Cells of NK Phenotype.

Chronic active Epstein-Barr virus (EBV) infection of T-cell and NK-cell type, systemic form (CAEBV-T/NK-S) is characterized by EBV T-cell and/or NK-cell proliferation with no changes suggesting malignancy. Therefore, when Hodgkin/Reed-Sternberg (HRS)-like cells are scattered in CAEBV-T/NK-S, it is more likely to be misdiagnosed as classic Hodgkin lymphoma. We encountered a case wherein the patient showed HRS-like cells with typical NK phenotype. Therefore, we further investigated 8 similar cases to provide clinicopathologic and genetic features and discuss their distinction from other related diseases. Clinically, all cases met the diagnostic criteria of CAEBV. Moreover, 4/8 patients had hemophagocytic lymphohistiocytosis. The median survival was 16 months (range, 5 to 35 mo). Pathologically, all lymph node samples had a remarkably similar morphology with scattered HRS-like cells surrounded by a mixture of small-sized lymphocytes, plasma cells, and macrophages that masqueraded classic Hodgkin lymphoma. Besides, erythrophagocytosis was detected in 4/11 samples. The HRS-like cells were positive for CD2, CD3p, CD30, CD56, GrB, and EBER-ISH, but negative for CD20, CD5, PAX-5, and LMP-1. The surrounding lymphocytes were mainly CD8 cytotoxic T cells, without obvious aberrant expression. In addition, all patients were polyclonal in the T-cell receptor γ rearrangement test. The harbored mutations were mainly in epigenetic modifiers, JAK-STAT signaling pathway, and apoptosis/cell cycle pathway, including SOCS1, DDX3X, and KMT2D, similar to other EBV-associated T/NK-cell lymphoproliferative disorders. Therefore, the evidence indicates that "HRS-like cells of NK phenotype" is a variant of CAEBV-T/NK-S. This study may raise awareness of such confounding CAEBV-T/N-S cases in clinical practice to avoid misdiagnosis and treatment delay.

A fulminant case of classical Hodgkin lymphoma: A diagnostic dilemma of Epstein-Barr virus-positive large B-cell neoplasms.

We report a fulminant case of classical Hodgkin lymphoma (CHL). The patient died only approximately 2 months after the onset of subjective symptoms. Autopsy specimens revealed atypical cells resembling Hodgkin and Reed-Sternberg (HRS) cells in a rich inflammatory background in various organs. There were marked, characteristic angiodestructive lesions from infiltrating HRS-like cells and numerous macrophages. The HRS-like cells were infected with Epstein-Barr virus (EBV), immunohistochemically positive for PAX5 and CD30, and negative for CD3, CD20, and ALK. Most B-cell markers other than PAX5 were negative, and the HRS-like cells also expressed cytotoxic molecules. Monoclonal rearrangement of immunoglobulin heavy chain was detected by PCR analysis. According to the 2016 WHO classification, we diagnosed mixed cellularity CHL. However, EBV-positive diffuse large B-cell lymphoma (DLBCL), not otherwise specified and EBV-positive B-cell lymphoma, unclassifiable with features intermediate between DLBCL and CHL were considered as differential diagnoses because both tumors are aggressive EBV-positive large B-cell neoplasms with reactive inflammatory cells and sometimes contains HRS-like cells. The clinical condition of the current case was closer to these two entities than to CHL. A diagnosis of EBV-positive large B-cell neoplasms was difficult because of overlapping morphological and immunohistochemical characteristics, but should be considered for prognosis.

An Epstein-Barr virus-positive classical Hodgkin lymphoma with exclusive sinusoidal growth pattern: An unusual morphologic variant.

Classical Hodgkin lymphoma (cHL) typically involves lymph node parenchyma, and a case with Hodgkin cells confined within nodal sinusoids is extremely rare. Herein we report a case of cHL with a sinusoidal growth pattern. This 15-year old patient presented with B symptoms and was found to have bilateral cervical lymphadenopathy and an anterior mediastinal mass. Biopsy of a cervical lymph node demonstrated cohesive clusters of Reed-Sternberg (RS)-like cells suggestive of sinusoidal growth with an extrasinusoidal mixed inflammatory cell infiltrate characteristic of the microenvironment seen in cHL. The RS cells/variants were positive for CD30 and CD15, and showed down-regulation of B-cell program and CD45, an immunophenotypic profile consistent with cHL. The sinusoidal growth pattern was also highlighted by EBV staining. To the best of our knowledge, this is the first case of EBV-positive cHL that displays a sinusoidal growth pattern. The patient was treated with children's high risk cHL chemotherapy protocol and responded well.

Clinicopathological Study of 30 Cases of Peripheral T-cell Lymphoma with Hodgkin and Reed-Sternberg-like B-cells from Japan.

The presence of Hodgkin and Reed-Sternberg (HRS)-like B-cells in peripheral T-cell lymphoma (PTCL) is rare and its clinicopathological features still remain unclear. Here, we describe 30 cases of PTCL with HRS-like B-cells from Japan. Twenty-three cases (77%) presented evidence of follicular T-helper phenotype (TFH) derivation: 12 were angioimmunoblastic T-cell lymphoma and 11 PTCL with TFH phenotype (PTCL-TFH). The remaining seven cases were diagnosed as PTCL, not otherwise specified (PTCL-NOS). Epstein-Barr virus (EBV) reactivation was detected in 25 cases (83%), but HRS-like B-cells were EBER in only 20 cases (67%). The median age at diagnosis was 77 years (range, 39-91 y), including 24 patients (80%) were older than 60 years of age. Most of the patients presented at an advanced clinical stage and were associated with higher risk according to the International Prognostic Index. The 3-year overall and progression-free survival rates were 44% and 27%, respectively. No significant clinicopathological differences were detected between PTCL-TFH, PTCL-NOS and the angioimmunoblastic cases. Cases with EBER HRS-like B-cells were associated with inferior overall and progression-free survival compared to those with EBER HRS-like B-cells, but the difference was not significant. In conclusion, HRS-like B-cells were found in a subset of T-cell lymphomas, especially in association with the TFH phenotype and EBV reactivation. These cells have a tendency to affect elderly patients and to be associated with advanced clinical stages and dismal prognosis. The EBV status of HRS-like B-cells does not seem to affect the clinicopathological features of this group of PTCLs.

The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis.

The pathogenesis of classical Hodgkin lymphoma (cHL) is still enigmatic, largely because its tumor cells, the so-called Hodgkin and Reed-Stenberg (HRS) cells, invariably reside in a prominent reactive microenvironment, are rare and therefore difficult to analyze. On the other hand, the broadly investigated cHL-derived cell lines are not unequivocally considered as suitable and representative models for this puzzling disease. Based on current knowledge, it appears that the cross talk between the tumor cells and the reactive infiltrate of the microenvironment is complex and that multiple mechanisms occur, making cHL a very heterogeneous disease. In 20-40% of cHL cases, HRS cells carry a monoclonal infection by Epstein Barr virus (EBV), which is considered a tumor-initiating factor. In these cases, EBV shows a latency type II infection pattern with the expression of latent membrane protein-1 (LMP-1), a viral oncoprotein that mimics CD40 activation. This scenario is particularly intriguing for the pathogenesis of cHL arising in HIV-infected patients, which, for still obscure reasons, is invariably EBV-associated with LMP-1 expression in HRS cells. Recent evidences are consistent with the occurrence of different pathogenic pathways variably triggered by virus infections (EBV and HIV), genetic alterations, and interactions with critical microenvironmental components. This review focuses on the different microenvironmental niches that characterize cHL of the general population as well as cases of HIV-infected patients. A more comprehensive understanding of the complex interplay existing between HRS and tumor microenvironment is pivotal for the development of more effective treatments, particularly for relapsed or refractory diseases.

Hodgkin lymphoma variant of Richter transformation: morphology, Epstein-Barr virus status, clonality, and survival analysis-with comparison to Hodgkin-like lesion.

Hodgkin/Reed-Sternberg (HRS) cells in the setting of chronic lymphocytic leukemia (CLL) exist in 2 forms: type I with isolated HRS cells in a CLL background (Hodgkin-like lesion) and type II with typical classic Hodgkin lymphoma, a variant of Richter transformation (CHL-RT). The clinical significance of the 2 morphological patterns is unclear, and their biological features have not been compared. We retrospectively reviewed 77 cases: 26 of type I and 51 of type II CHL-RT; 3 cases progressed from type I to type II. We examined clinical features, Epstein-Barr virus (EBV) status, and clonal relatedness after microdissection. Median age for type I was 62 years versus 73 years for type II (P=.01); 27% (type I) versus 73% (type II) had a history of CLL. HRS cells were positive for EBV in 71% (55/77), similar in types I and II. Clonality analysis was performed in 33 cases (type I and type II combined): HRS cells were clonally related to the underlying CLL in 14 and unrelated in 19. ZAP-70 expression of the CLL cells but not EBV status or morphological pattern was correlated with clonal relatedness: all 14 clonally related cases were ZAP-70 negative, whereas 74% (14/19) of clonally unrelated cases were ZAP-70 positive. Overall median survival (types I and II) after diagnosis was 44 months. Advanced age was an adverse risk factor for survival, but not histologic pattern, type I versus type II. HRS-like cells in a background of CLL carries a similar clinical risk to that of CHL-RT and may progress to classic Hodgkin lymphoma in some cases.

Pretreatment whole blood Epstein-Barr virus-DNA is a significant prognostic marker in patients with Hodgkin lymphoma.

Epstein-Barr virus (EBV) in the peripheral blood has become a significant predictor of clinical outcomes in EBV-associated Hodgkin lymphoma (HL). However, due to its relative rarity, prevalence and prognostic role of circulating EBV-DNA has not been well established in Asian patients. Seventy patients with newly diagnosed HL were prospectively registered between October 2007 and January 2013, and underwent pretreatment whole blood (WB) EBV-DNA quantitation using real-time polymerase chain reaction (RT-PCR). WB EBV-DNA in baseline and serial RT-PCR within 1 year were investigated. Clinicopathologic parameters of the patients according to pretreatment WB EBV-DNA were also explored. Twelve patients (17.1 %) demonstrated WB EBV-DNA(+), which was significantly associated to older age, advanced stages, frequent involvements of extranodal sites, low serum albumin and hemoglobin levels, and high international prognostic scores ≥2. Three-year event-free survival (EFS) and overall survival (OS) were significantly inferior in patients with pretreatment WB EBV-DNA(+) (53.5 vs 67.0 and 65.6 vs 90.2 %) (p < 0.032 and <0.01). Negatively conversed EBV-DNA within 1 year after chemotherapy also significantly affected favorable EFS (p < 0.01). Taken together, pretreatment WB EBV-DNA(+) may be a significant predictor of inferior EFS and OS over EBV-encoded RNA in situ hybridization (EBER-ISH)(+) in Korean patients with HL. Serial EBV-DNA monitoring following chemotherapy also seems helpful to predict survival outcomes.

MUM-1 expression differentiates AITL with HRS-like cells from cHL.

MUM1 is a member of the interferon regulatory factor family of transcription factors. It is normally expressed in plasma cells, late B cells, and activated T cells, and has been described in several B-cell malignancies and some T-cell neoplasms. The aim of our study was to evaluate the role of MUM-1/IRF4 protein in differentiating angioimmunoblastic T cell lymphoma (AITL) with Hodgkin/Reed-Sternberg (HRS)-like cells from cHL. We identified 12 cases of AITL with HRS-like cells and 24 cases of cHL from March 2013 to November 2014. IHC for MUM-1/IRF4 protein was performed on the tissue of these cases and some relevant positive and negative controls. MUM-1 was expressed in HRS-like cells and some neoplastic T-cells in AITL with HRS-like cells (12/12, 100%) and formed the rosettes around the HRS-like cells (12/12, 100%), expressed in HRS cells in classic Hodgkin Lymphoma (cHL) (24/24, 100%) and just one case formed rosettes around the HRS cells (1/24, 4.2%). Based on the results, MUM-1 could be a useful marker for the differential diagnosis between AITL with HRS-like cells and cHL.

Epstein-Barr virus infection is inversely correlated with the expression of retinoblastoma protein in Reed-Sternberg cells in classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) is characterized by few neoplastic Hodgkin/Reed-Sternberg (H/RS) cells in a background of intense inflammatory infiltrate. Epstein-Barr virus (EBV) has been shown to affect cell cycle and regulation of apoptosis. In total, 82 cases of cHL were studied. Five- micrometer sections were prepared and stained with haematoxylin and eosin and immunohistochemical streptavidin-biotin methods for EBV-LMP-1, pRb, ki-67 and cleaved caspase-3. In-situ hybridization for EBV encoded RNA was used to confirm the detection of EBV in H/RS cells. There were 45 nodular sclerosis, 28 mixed cellularity, 4 lymphocyte-rich, and 5 lymphocyte depletion subtypes in this series of cases. EBV and pRb were detected in 55% (46/82) and 64% (50/82) of the cases respectively. EBV was detected in 78% (25/32) of pRb-negative cases and 81% (29/36) of EBV-negative cases are pRb-positive. A statistically significant inverse relationship was observed between the presence of EBV and expression of pRb (P = 0.001). In conclusion, EBV infection is inversely correlated with pRb in H/RS cells in cHL.

Epstein-Barr virus infection correlates with the expression of COX-2, p16(INK4A) and p53 in classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL), a germinal-center related B cell neoplasm in almost all cases, is characterized by scarcity of the neoplastic Hodgkin/Reed-Sternberg (H/RS) cells. Epstein-Barr virus (EBV) has been shown to affect cell cycle and regulation of apoptosis. In total, 95 cases of cHL were studied. Five-micrometer sections were prepared and stained with hematoxylin and eosin and immunohistochemical streptavidin-biotin methods for EBV-LMP-1, COX-2, p53, p16, ki-67 and cleaved caspase-3. In-situ hybridization for EBV encoded RNA was used to confirm the detection of EBV in H/RS. There were 49 nodular sclerosis, 32 mixed cellularity, 8 lymphocyte-rich, and 6 lymphocyte-depleted subtypes in this series of cases. EBV, COX-2, p16(INK4A) and p53 were detected in 55% (52/95), 64% (61/95), 62% (59/95), and 65% (62/95) of the cases respectively. EBV was detected in 62% (38/61), 70% (41/59), and 69% (43/62) of COX2, p16 and p53 positive cases respectively. On the other hand, EBV-non-infected cases of cHL are associated with 59% (20/34), 69% (25/36), and 73% (24/33) of COX2, p16 and p53 negative cases respectively. In conclusion, EBV infection is associated with the expression of COX-2, p16(INK4A) and p53. EBV might be the dominant factor in determining the expression of these three proteins.

[Factors involved in host-pathogen interaction for the risk of Hodgkin lymphoma induced by Epstein Barr virus]. / Factores que participan en la interacción huésped-agente patógeno en el riesgo de Linfoma de Hodgkin inducido por el virus Epstein Barr.

Hodgkin lymphoma (HL) is a neoplasm characterized by malignant cells called Reed Sternberg and Hodgkin's cells in the lymphatic system. Such cells comprise 1% of the tumor while the remainder is made up of lymphocytes, histiocytes, eosinophils and plasma non-neoplastic cells. The annual global incidence of HL is 3-10/100,000 inhabitants and is most commonly found in young adults. The mechanism by which cell transformation is accomplished is not entirely clear; however, some evidences suggest that oncogenic viruses like the Epstein Barr virus (EBV) may have a high impact on the pathogenesis of lymphoproliferation. Genetic and environmental factors could be involved, since it has been found a high incidence of HL among members of the same family. In Mexico, there have been studies to determine the prevalence of EBV in patients with HL and found the presence of this virus in up to 64.2% of the cases. EBV has been detected in the Reed Sternberg cells and Hodgkin cells in 50% of cases of classical HL. There is not a satisfactory explanation for this, but it has been proposed that geographic and immunological variabilities play a role in the positivity of EBV in HL. However, despite recent advances in the field, there is insufficient evidence to show a clear association between host factors, environment and pathogens, and the risk of lymphoproliferation leading to the development of HL. This review aims to give an overview about the risk factors that influence the interaction of host, pathogens and environment in the etiology of HL.

Matrix metalloproteinase-9 expression by Hodgkin-Reed-Sternberg cells is associated with reduced overall survival in young adult patients with classical Hodgkin lymphoma.

Previous studies have investigated the prognostic relevance of MMP9 in classical Hodgkin lymphoma (cHL), with negative results. However, we have found that MMP9 immunoistochemical expression by Hodgkin-Reed-Sternberg cells is associated with reduced overall survival in a subset of young adult Brazilian patients diagnosed with cHL. Additionally, we have observed that MMP9 expression by neoplastic cells in cHL is associated with EBV positivity. These results may support a rational basis for additional studies on the role of this metalloproteinase as a target for therapy in classical Hodgkin lymphoma.

Epstein-Barr virus (EBV) positive classical Hodgkin lymphoma of Iraqi children: an immunophenotypic and molecular characterization of Hodgkin/Reed-Sternberg cells.

BACKGROUND: Classical Hodgkin lymphoma (cHL) in children is often associated with EBV infection, more commonly in developing countries. PROCEDURE: Here we describe the histological, immunohistochemical, and molecular features of 57 cases of HL affecting Iraqi children under 14 years of age. RESULTS: Histologically, 51 cases were classified as cHL of Mixed Cellularity and Nodular Sclerosis subtypes (MC = 69%; NS = 31%), and 6 cases as Nodular Lymphocyte Predominant HL (NLP-HL). EBV infection of H/RS cells was demonstrated in 44 of 51 cases of cHL (86%), and was more common in MC than in NS (97% vs. 63%; P = 0.0025). The immunophenotypic profile of H/RS cells was similar in MC and NS, and was not influenced by EBV infection; H/RS cells were consistently positive for PAX-5 and to a lesser degree for other B cell markers including CD20/CD79a, OCT-2, and BOB-1. Clonal IGH rearrangements were detected in 14 of 38 cHL (37%), with no significant difference between MC and NS cases, and with no association with the EBV status. Oligoclonal/monoclonal TCRγ rearrangements were present in 28 of 38 cases (74%), suggestive of restricted T cell responses. CONCLUSIONS: Our findings indicate that cHL occurring in Iraqi children is characterized by immunohistochemical and molecular features undistinguishable from those present in cHL occurring elsewhere in the world. Moreover, the high incidence of EBV-infected H/RS cells and frequent occurrence of restricted T cell responses might be indicative of a defective local immune response perhaps related to the very young age of the children.

Factores que participan en la interacción huésped-agente patógeno en el riesgo de Linfoma de Hodgkin inducido por el virus Epstein Barr / Factors involved in host-pathogen interaction for the risk of Hodgkin lymphoma induced by Epstein Barr virus

El linfoma de Hodgkin (LH) es una neoplasia del sistema linfático. La incidencia mundial anual del LH es de 3-10/100,000 habitantes. El mecanismo mediante el cual se lleva a cabo la transformación celular no es completamente claro; sin embargo, algunas evidencias parecen indicar que ciertos virus oncogénicos como el virus Epstein Barr (VEB), pueden tener alto impacto en la patogénesis de la linfoproliferación. También algunos factores genéticos y ambientales pueden estar involucrados, pues se ha encontrado una alta incidencia de casos de LH entre individuos de una misma familia que comparten características genéticas y conviven en un mismo ambiente. En México se han realizado estudios encaminados a conocer la prevalencia del VEB en pacientes con LH y se ha encontrado la presencia de este virus hasta en el 64,2%. El VEB ha sido detectado en las Células Reed Sternberg (CRS) y en Células de Hodgkin (CH) en el 50% de los casos de LH clásico. No se ha dado hasta ahora una explicación satisfactoria, pero se ha propuesto que la variabilidad geográfica y la variabilidad inmunológica desempeñan un papel determinante en la positividad del VEB en LH. A pesar de los avances que hasta ahora se tienen, no existen suficientes evidencias que permitan establecer una clara asociación entre los factores del huésped, el medio ambiente y el agente patógeno en el riesgo de la linfoproliferación que conduce al desarrollo de LH. La presente revisión tiene como objetivo analizar algunos de los factores de riesgo que influyen durante la interacción huésped, agente patógeno y medio ambiente en la etiología del LH.

Hodgkin lymphoma (HL) is a neoplasm characterized by malignant cells called Reed Sternberg and Hodgkin’s cells in the lymphatic system. Such cells comprise 1% of the tumor while the remainder is made up of lymphocytes, histiocytes, eosinophils and plasma non-neoplastic cells. The annual global incidence of HL is 3-10/100,000 inhabitants and is most commonly found in young adults. The mechanism by which cell transformation is accomplished is not entirely clear; however, some evidences suggest that oncogenic viruses like the Epstein Barr virus (EBV) may have a high impact on the pathogenesis of lymphoproliferation. Genetic and environmental factors could be involved, since it has been found a high incidence of HL among members of the same family. In Mexico, there have been studies to determine the prevalence of EBV in patients with HL and found the presence of this virus in up to 64.2% of the cases. EBV has been detected in the Reed Sternberg cells and Hodgkin cells in 50% of cases of classical HL. There is not a satisfactory explanation for this, but it has been proposed that geographic and immunological variabilities play a role in the positivity of EBV in HL. However, despite recent advances in the field, there is insufficient evidence to show a clear association between host factors, environment and pathogens, and the risk of lymphoproliferation leading to the development of HL. This review aims to give an overview about the risk factors that influence the interaction of host, pathogens and environment in the etiology of HL.

Suppression of the LMP2A target gene, EGR-1, protects Hodgkin's lymphoma cells from entry to the EBV lytic cycle.

Hodgkin's lymphoma is unusual among B cell lymphomas, in so far as the malignant Hodgkin/Reed-Sternberg (HRS) cells lack a functional B cell receptor (BCR), as well as many of the required downstream signalling components. In Epstein-Barr virus (EBV)-positive cases of Hodgkin's lymphoma, HRS cells express the viral latent membrane proteins (LMP)-1 and -2A. LMP2A is thought to contribute to the pathogenesis of Hodgkin's lymphoma by providing a surrogate BCR-like survival signal. However, LMP2A has also been shown to induce the virus-replicative cycle in B cells, an event presumably incompatible with lymphomagenesis. In an attempt to resolve this apparent paradox, we compared the transcriptional changes observed in primary HRS cells with those induced by LMP2A and by BCR activation in primary human germinal centre (GC) B cells, the presumed progenitors of HRS cells. We found a subset of genes that were up-regulated by both LMP2A expression and BCR activation but which were down-regulated in primary HRS cells. These genes included EGR1, an immediate-early gene that is required for BCR-induced entry to the virus-replicative cycle. We present data supporting a model for the pathogenesis of EBV-positive Hodgkin's lymphoma in which LMP2A-expressing HRS cells lacking BCR signalling functions cannot induce EGR1 and are consequently protected from entry to the virus lytic cycle. The primary microarray data are available from GEO (http://www.ncbi.nlm.nih.gov/geo/) under series Accession No 46143.