Overexpression of Activation-Induced Cytidine Deaminase in MTX- and Age-Related Epstein-Barr Virus-Associated B-Cell Lymphoproliferative Disorders of the Head and Neck

Recent research has shown that activation-induced cytidine deaminase (AID) triggers somatic hypermutation and recombination, in turn contributing to lymphomagenesis. Such aberrant AID expression is seen in B-cell leukemia/lymphomas, including Burkitt lymphoma which is associated withc-myctranslocation. Moreover, Epstein-Barr virus (EBV) latent membrane protein-1 (LMP-1) increases genomic instability through early growth transcription response-1 (Egr-1) mediated upregulation of AID in B-cell lymphoma. However, few clinicopathological studies have focused on AID expression in lymphoproliferative disorders (LPDs). Therefore, we conducted an immunohistochemical study to investigate the relationship between AID and LMP-1 expression in LPDs (MTX-/Age-related EBV-associated), including diffuse large B-cell lymphomas (DLBCLs). More intense AID expression was detected in LPDs (89.5%) than in DLBCLs (20.0%), and the expression of LMP-1 and EBER was more intense in LPDs (68.4% and 94.7%) than in DLBCLs (10.0% and 20.0%). Furthermore, stronger Egr-1 expression was found in MTX/Age-EBV-LPDs (83.3%) than in DLBCLs (30.0%). AID expression was significantly constitutively overexpressed in LPDs as compared with DLBCLs. These results suggest that increased AID expression in LPDs may be one of the processes involved in lymphomagenesis, thereby further increasing the survival of genetically destabilized B-cells. AID expression may be a useful indicator for differentiation between LPDs and DLBCLs.

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Age-related Epstein-Barr virus (EBV)–associated B-cell lymphoproliferative disorders: comparison with EBV-positive classic Hodgkin lymphoma in elderly patients

Blood ◽

10.1182/blood-2008-06-164806 ◽

2009 ◽

Vol 113 (12) ◽

pp. 2629-2636 ◽

Cited By ~ 113

Author(s):

Naoko Asano ◽

Kazuhito Yamamoto ◽

Jun-Ichi Tamaru ◽

Takashi Oyama ◽

Fumihiro Ishida ◽

...

Keyword(s):

B Cell ◽

Hodgkin Lymphoma ◽

Epstein Barr Virus ◽

Age At Onset ◽

B Cell Lymphoma ◽

Female Ratio ◽

Barr Virus ◽

Age Related ◽

Classic Hodgkin Lymphoma ◽

Epstein Barr

Abstract Age-related Epstein-Barr virus–associated B-cell lymphoproliferative disorder (aEBVLPD) is a disease group characterized by EBV-associated large B-cell lymphoma in elderly without predisposing immunodeficiency. In nearly one- third of cases, aEBVLPD occurs as a polymorphous subtype with reactive cell-rich components, bearing a morphologic similarity to classic Hodgkin lymphoma (cHL). The aim of this study was to clarify clinicopathologic differences between the polymorphic subtype of aEBVLPD (n = 34) and EBV+ cHL (n = 108) in patients aged 50 years or older. Results showed that aEBVLPD was more closely associated with aggressive clinical parameters than cHL, with a higher age at onset (71 vs 63 years); lower male predominance (male-female ratio, 1.4 vs 3.3); and a higher rate of involvement of the skin (18% vs 2%), gastrointestinal tract (15% vs 4%), and lung (12% vs 2%). aEBVLPD was histopathologically characterized by a higher ratio of geographic necrosis, greater increase (> 30%) in cytotoxic T cells among background lymphocytes, higher positivity for CD20 and EBNA2, and absence of CD15 expression. As predicted by the clinical profile, aEBVLPD had a significantly poorer prognosis than EBV+ cHL (P < .001). The polymorphous subtype of aEBVLPD constitutes an aggressive group with an immune response distinct from EBV+ cHL, and requires the development of innovative therapeutic strategies.

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Epstein-Barr Virus Positive B-Cell Lymphoproliferative Disorder of the Gastrointestinal Tract

Cancers ◽

10.3390/cancers13153815 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3815

Author(s):

Eri Ishikawa ◽

Akira Satou ◽

Masanao Nakamura ◽

Shigeo Nakamura ◽

Mitsuhiro Fujishiro

Keyword(s):

B Cell ◽

Lymphoproliferative Disorder ◽

Epstein Barr Virus ◽

B Cell Lymphoma ◽

Biological Behavior ◽

Routine Practice ◽

Gi Tract ◽

Barr Virus ◽

Age Related ◽

Epstein Barr

Epstein-Barr virus positive B-cell lymphoproliferative disorder (EBV+ B-LPD) encompasses a broad clinicopathological spectrum and distinct clinical behavior that relatively favors the gastrointestinal (GI) tract. In this review, we provide an update on the clinicopathological features and biological behavior of EBV-positive mucocutaneous ulcer (EBVMCU) and primary EBV+ diffuse large B-cell lymphoma (DLBCL) of the GI tract. EBVMCU is a newly recognized entity but well known as an indolent and self-limited EBV+ B-LPD occurring in various immunodeficiencies. In contrast, EBV+ DLBCL constitutes the largest group of EBV+ B-LPDs and is regarded as an aggressive neoplasm. These two distinct diseases have historically been distinguished in the reappraisal of age-related EBV-associated B-LPDs but are challenging in routine practice regarding their differential diagnostic and therapeutic approaches. An increasing number of reports indicate that they are epidemiologically prevalent beyond western and eastern countries, but their comprehensive analysis is still limited. We also describe the PD-L1 positivity of tumorous large cells and non-malignant immune cells, which is relevant for the prognostic delineation among patients with primary DLBCL of the GI tract with and without EBV on tumor cells.

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Age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorders in elderly White patients

Histopathology ◽

10.1111/j.1365-2559.2010.03605.x ◽

2010 ◽

Vol 57 (2) ◽

pp. 320-323 ◽

Cited By ~ 1

Author(s):

Stanislas Nimubona ◽

Marc Bernard ◽

Sophie De Guibert ◽

Hélène Duval ◽

Sylvie Caulet-Maugendre ◽

...

Keyword(s):

B Cell ◽

Epstein Barr Virus ◽

Lymphoproliferative Disorders ◽

Barr Virus ◽

Age Related ◽

Epstein Barr ◽

White Patients

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Epstein-Barr virus nuclear antigen 2 inhibits AID expression during EBV-driven B-cell growth

Blood ◽

10.1182/blood-2006-05-021303 ◽

2006 ◽

Vol 108 (12) ◽

pp. 3859-3864 ◽

Cited By ~ 30

Author(s):

Stephanie Tobollik ◽

Linda Meyer ◽

Maike Buettner ◽

Sandra Klemmer ◽

Bettina Kempkes ◽

...

Keyword(s):

Cell Growth ◽

B Cell ◽

Epstein Barr Virus ◽

Somatic Hypermutation ◽

Cytidine Deaminase ◽

Inhibitory Effect ◽

Nuclear Antigen ◽

Germinal Center Reaction ◽

Barr Virus ◽

Epstein Barr

Abstract Somatic hypermutation and class-switch recombination in germinal centers critically depend on activation-induced cytidine deaminase (AID). Deregulation of AID may lead to the aberrant activation or persistence of both genetic processes, thus contributing to the pathogenesis of B-cell lymphomas by mistargeted mutagenesis or recombination. The Epstein-Barr virus (EBV) establishes an asymptomatic latent infection in more than 90% of the human population, but it has also been linked to lymphomagenesis. A cooperative relationship of EBV and the germinal center reaction during the establishment of viral persistence has been postulated, but the contribution of EBV latent genes to the respective genetic events remains to be investigated in detail. In the present study, we show that activation of the EBV growth program has a clear inhibitory effect on AID expression, due to a negative effect of the master transcription factor of this program, EBNA2. This mechanism may counterbalance AID induction by the LMP1 protein, in order to prevent deleterious genetic changes during EBV-induced B-cell growth. EBNA2-mediated AID inhibition also provides a molecular explanation for the previously observed differences in somatic hypermutation activity in EBV-associated lymphoproliferative diseases, thus pointing to a crucial mechanism of EBV-mediated regulation of genomic integrity.

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Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells

Journal of Experimental Medicine ◽

10.1084/jem.20160120 ◽

2016 ◽

Vol 213 (6) ◽

pp. 921-928 ◽

Cited By ~ 36

Author(s):

Jens S. Kalchschmidt ◽

Rachael Bashford-Rogers ◽

Kostas Paschos ◽

Adam C.T. Gillman ◽

Christine T. Styles ◽

...

Keyword(s):

B Cells ◽

Epstein Barr Virus ◽

Nuclear Protein ◽

Somatic Hypermutation ◽

Cytidine Deaminase ◽

Regulatory Elements ◽

Definitive Evidence ◽

Barr Virus ◽

Activation Induced Cytidine Deaminase ◽

Epstein Barr

Activation-induced cytidine deaminase (AID), the enzyme responsible for induction of sequence variation in immunoglobulins (Igs) during the process of somatic hypermutation (SHM) and also Ig class switching, can have a potent mutator phenotype in the development of lymphoma. Using various Epstein-Barr virus (EBV) recombinants, we provide definitive evidence that the viral nuclear protein EBNA3C is essential in EBV-infected primary B cells for the induction of AID mRNA and protein. Using lymphoblastoid cell lines (LCLs) established with EBV recombinants conditional for EBNA3C function, this was confirmed, and it was shown that transactivation of the AID gene (AICDA) is associated with EBNA3C binding to highly conserved regulatory elements located proximal to and upstream of the AICDA transcription start site. EBNA3C binding initiated epigenetic changes to chromatin at specific sites across the AICDA locus. Deep sequencing of cDNA corresponding to the IgH V-D-J region from the conditional LCL was used to formally show that SHM is activated by functional EBNA3C and induction of AID. These data, showing the direct targeting and induction of functional AID by EBNA3C, suggest a novel role for EBV in the etiology of B cell cancers, including endemic Burkitt lymphoma.

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