Deficiency of the proapoptotic SAP function in X-linked lymphoproliferative disease aggravates Epstein-Barr virus (EBV) induced mononucleosis and promotes lymphoma development.
ABSTRACT The lack of functional SAP protein, a consequence of mutation or deletion of the SH2D1A gene is the cause of X-linked lymphoproliferative disease (XLP). Others and we have shown that SAP can be involved in apoptosis. Activation induced apoptosis plays a pivotal role in the termination of the lymphocyte proliferation in infectious mononucleosis IM. This mechanism is inefficient in the XLP patients. Primary EBV infection of boys with XLP leads therefore to fulminant, often even fatal disease. In addition, the condition predisposes to considerably elevated incidence of lymphomas. Chromosomal translocation that juxtaposes one of the three immunoglobulin loci to the c-myc proto-oncogene is the hallmark of Burkitt lymphomas (BL), whether they carry the Epstein-Barr Virus (EBV) or not. Ig/myc translocations occur as rare accidents of normal B lymphocyte differentiation. The activated myc would drive the cells to proliferate, however unless protected, the cells become prone to apoptosis. Our results with BL derived cell lines suggest that the fate of the precursor cells is decided by the expression of the proapototic SAP and EBV infection. We found SAP expression in eight of ten EBV carrying, but none of nine EBV negative BL lines. Therefore it seems that the apoptosis prone Ig/myc translocation carrying EBV negative precursors of BL can grow into lymphomas only if they do not express the proapoptotic SAP while SAP expressor, but EBV positive cells can survive and proliferate. This is probably due to the antiapoptotic function of EBNA-1 and the proliferation induced by activated myc.
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ABSTRACT: The Epstein-Barr virus (EBV) is the first identified human virus with a proven association with the pathogenesis of cancer. To maintain the integrity of the viral genome and to "get out" of the control of the host immune system, in the phase of the latent infection EBV shows the expression of several genes, including genes for six nuclear antigens, three latent membrane proteins, two short non-coding RNAs, and BamHI-A rightward transcripts. The different patterns of expression of these latent genes determine the occurrence of different types of latency in the pathogenesis of particular malignancies. One of the most important features of EBV is its ability to infect various cell types and the consequent variety of diseases. It has been shown that in humans, EBV infection may lead to the development of cancers, including those derived from hematopoietic cells. Although cases of T-cell and epithelial cell infections have been documented, EBV is characterized mainly by tropism for B lymphocytes, and under certain conditions their infection may result in transformation to B-cell lymphoma. This article discusses the mechanisms leading to the development of EBV-dependent lymphomas, and briefly characterizes these diseases. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.Seminars in Oncology 12/2014; 12(2). DOI:10.1053/j.seminoncol.2014.12.030 · 3.94 Impact Factor
British Journal of Haematology 07/2013; DOI:10.1111/bjh.12454 · 4.96 Impact Factor
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ABSTRACT: Abstract Observational and clinical studies have associated increased cancer risks with primary or acquired immunodeficiencies, autoimmunity, and use of immunotherapies to treat chronic inflammation (e.g. autoimmunity) or support organ engraftment. Understanding of the relationship between immune status and cancer risk is generally grounded in two juxtaposing paradigms: that the immune system protects the host via surveillance of tumors and oncogenic viruses (e.g. immunosurveillance model) and that chronic inflammation can augment tumor growth and metastasis (inflammation model). Whereas these models support a role of immune status in many cancers, they are insufficient to explain the disproportionate increase in B-cell lymphoma risk observed across patient populations with either chronic immunosuppression or inflammation. Evaluation for the presence of Epstein-Barr virus (EBV) in lymphomas obtained from various populations demonstrates a variable role for the virus in lymphomagenesis across patient populations. An evaluation of the DNA alterations found in lymphomas and an understanding of B-cell ontogeny help to provide insight into the unique susceptibility of lymphocytes, primarily B-cells, to oncogenic transformation. EBV-independent B-cell oncogenic transformation is driven by chronic antigenic stimulation due to either inflammation (as seen in patients with autoimmune disease or a tissue allograft) or to unresolved infection (as seen in immunosuppressed patients), and the transformation arises as a result of DNA damage from genomic recombination and mutation during class switching and somatic hypermutation. This model explains the increased background rate of lymphoma in some patients with autoimmunity, and highlights the challenge of resolving the confounding that occurs between disease severity and use of targeted immunotherapies to treat chronic inflammation. The ability to distinguish between disease- and treatment-related risk of lymphoma and an appreciation of the etiology of B-cell transformation is central to an improved risk assessment by scientists, clinicians and regulators, including the approval, labeling, and chronic use of immunotherapies.Journal of Immunotoxicology 06/2013; DOI:10.3109/1547691X.2013.798388 · 1.91 Impact Factor