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In addition to the jaw, other common sites include ovary, mammary gland, liver, intestine and kidneys. BL is rapidly fatal if untreated, although chemotherapy can provide good long-term survival.</p> <p>Histologically BL consists of rapidly proliferating, small, non-cleaved B-cells infiltrated with large, pale staining histiocytes which give the classic "starry sky" pattern.</p> <h5>Genetic abnormalities</h5> <p>All BL tumors, whether EBV associated or not, show one or more chromosomal translocations (8:14, 8:2 or 8:22) which brings <i>c-myc</i> oncogene on chromosome 8 under the influence of Ig (immunoglobulin) heavy (chr. 14) or light (kappa on chr. 2, lambda on chr. 22) chain promoters and causes its constitutive expression. </p> <p><i>c-myc</i> is a cellular oncogene which drives the cell to continuous proliferation and inhibits differentiation. Thus, this translocation is regarded as pivotal in BL development. </p> <h5>Gene expression</h5> <p>Most EBV-positive cases exhibit highly restrictive pattern of expression of latent encoded proteins, only expressing EBNA-1 and EBERs (<em>latency I</em>). However, it was recently reported that some cases, in addition to EBNA-1 and EBERs, express EBNA-3A, EBNA-3B, EBNA-3C, and EBNA-LP (EBNA leader protein) but still lack EBNA-2 and Latent Membrane Proteins (LMPs). </p> <a href="#top">Back to top</a> <img src="../IMG/Nemose-ruler.png" alt="Nemose" /> <h3>Role of Epstein-Barr virus in sustaining BL</h3> <h5>Viral plasmids are distributed unevenly but only EBV+ host cells survive</h5> <p>Epstein-Barr virus exists in latently infected tumor cells in form of extra-chromosomal circular DNA (episome or plasmid). For cultured cells transfected with foreign DNA, maintenance of the DNA is a burden unless it does not encode genes that are necessary for the cells' survival and proliferation in adverse environments (for example, antibiotic resistance). </p> <p>It was found that not all EBV plasmids are duplicated each cell cycle which leads to a loss of EBV plasmids from some of the daughter cells. EBV-associated human tumor cells remain EBV-positive throughout the cancer development, thus demonstrating that EBV sustains the tumor cells <i>in vivo</i>. To provide selective advantages to infected cells the virus can promote their proliferation or/and inhibit apoptosis. Most current evidence indicates that EBV minimally blocks apoptosis in Burkitt's lymphoma's cells. </p> <h5>Unorthodox host-parasite relationship: host cells are using virus to their advantage</h5> <p>Traditionally, viruses are considered to be obligate cellular parasites: they infect the host's cell, hijack the cell's resources, produce progeny leading to cell's death by lysis, by apoptosis, or by immune response. But in case of carcinogenic viruses, the roles appear to be reversed: by retaining viral genes the tumor cell acquires properties that give it selective advantage over uninfected cells wherereas the virus is usually incapable to reproduce. </p> <h5>EBV in Burkitt's lymphoma is not lymphoproliferaive</h5> <p> EBV is known for its ability to drive resting, primary B cells to proliferate (a process referred as <em>transformation</em>). The <em>Latent Membrane Protein 1 (LMP1)</em>, a classical oncogene that alters cellular cycle's signaling pathways, was found to be responsible for B-cell transformation and subsequent proliferation and typically its withdrawal causes transformed cells derived from Post-Transplant Lymphoproliferative Disorder (PTLD) or Hodgkin's lymphomas to cease proliferation. </p> <p>Burkitt's lymphomas are aggressive tumors but they do not express LMP1. In addition, none of the pathways central to LMP1-mediated proliferation (for example, JAK/STAT or AP-1 pathways) are activated in Burkitt's lymphoma. It is suggested that LMP1 is not expressed in BL both because it is immunogenic, and because it does not provide an optimal proliferative stimulus for the evolving tumor, which is provided by the translocated <i>c-myc</i> oncogene, a hallmark of all Burkitt's lymphomas. The chromosomal translocations that are characteristic of all BLs, is the primary oncogenic event in the pathogenesis of BL irrespective of the association with EBV, however, EBV infection (specifically, EBNA1 expression) together with other contributing factors (such as HIV and malaria) might increase the likelihood of genetic accidents giving rise to the translocations as well as providing further complementary support to mutated cells.</p> <h5>EBV blocks apoptosis in B cells</h5> <p>Normal B-lymphocytes are controlled by multiple regulators of apoptosis. Reflecting their cells of origin, Burkitt's lymphomas are also prone to apoptosis. Moreover, misregulated <i>c-myc</i> sensitizes cells to apoptosis as well. A defining histopathological pattern of Burkitt's lymphoma is "starry sky" appearance, resulting from the infiltration of the tumor by phagocytic macrophages cleaning out apoptotic tumor cells. Despite this, Burkitt's lymphomas grow extremely rapidly.</p> <p>Most viral genes expressed latently in B cells have been reported under some conditions to block several pro-apoptotic signaling pathways (for example, Bim, p53, PUMA). EBNA1 expressed in all EBV-positive Burkitt's lymphomas is considered principal anti-apoptotic agent. The viral RNAs (EBERs and miRNAs) have also been demonstrated to possess anti-apoptotic activity and are ubiquitously expressed in Burkitt's lymphomas. </p> <h5>EBV shields BL from host's immune response</h5> <p>The immune system is capable of generating both CD4+ and CD8+ T-cell responses to several latent and lytic phase EBV-associated antigens (Ags), such as LMP1, LMP2, EBNA2, and EBNA3. Unfortunately, BL cells generally express only the EBNA1 protein (<em>Latency 1</em> program, <a href="EBV-persistence.html" class="external">EBV latency and persistence</a>), which is poorly antigenic and has little to no HLA class response. Many aspects of BL's capabilities to evade the host's immune response are described in review by God JM &amp; Haque A., 2010 (see references below). </p> <a href="#top">Back to top</a> <img src="../IMG/Nemose-ruler.png" alt="Nemose" /> <img src="../IMG/Burkitt-lymphoma-pathogenesis.png" alt="Burkitt's lymphoma pathogenesis" /> <a href="#top">Back to top</a> <img src="../IMG/Nemose-ruler.png" alt="Nemose" /> <h3>References</h3> <ul> <li> <p> Mwakigonja AR, Kaaya EE, Mgaya EM. <em>Malignant lymphomas (ML) and HIV infection in Tanzania</em> <i><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2438337/?tool=pmcentrez" target="_blank" class="external">J Exp Clin Cancer Res. 2008; 27(1): 9.</a></i> </p> <p> <img src="../IMG/Burkitt-lymphoma-tissue-section.jpg" alt="Burkitt's lymphoma tissue section" /></p> <p> <em> Burkitt's lymphoma tissue section.</em> Briefly, tissue sections (5 ¼ thick) were stained with Hematoxylin and Eosin (H &amp; E). Section of a BL; note the "starry-sky" appearance due to tingible-body macrophages. </p> </li> <li> <p> Vereide D, Sugden B. <em>Proof for EBV's sustaining role in Burkitt's lymphomas.</em> <i><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789873/?tool=pubmed#FN2" target="_blank" class="external">Semin Cancer Biol. 2009 Dec;19(6):389-93. </a> </i> <i><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2438337/?tool=pmcentrez" target="_blank" class="external">J Exp Clin Cancer Res. 2008; 27(1): 9.</a></i> </p> <p> <img src="../IMG/EBV-propagation-in-Burkitt-lymphoma.jpg" alt="EBV propagation in- Burkitt lymphoma" /></p> <p> <em>A model of the synthesis and partitioning of EBV plasmids</em> Shown is one cell in the G2 phase of the cell cycle with EBV plasmids identified with letters. Four plasmids were duplicated in the prior S phase to yield co-localized pairs of plasmids (AA1, BB1, CC1, and DD1); one was not (E). Studies with EBV plasmids visualized in live cells have shown that 16% of the plasmids fail to be duplicated each S-phase [21]. These studies have also shown that during mitosis (M-phase) 88% of the co-localized plasmids are partitioned symmetrically. This partitioning is represented here as plasmids A and A1, B and B1, and C and C1 each being distributed to separate daughter cells in G1 phase. The 12% of the co-localized plasmids that do not partition symmetrically, represented by D and D1, and the 16% of the plasmids that are not duplicated in S phase, represented by E, partition randomly. In the example depicted here, all three plasmids (D, D1, A) have been distributed to the same daughter cell. These defects in synthesis and partitioning lead to daughter cells having increased numbers of plasmids as shown for the upper cell in G1 and decreased numbers of plasmids as shown for the lower cell in G1 relative to the parental cell in G2. The defect in plasmid synthesis leads to the loss of plasmids from a population of proliferating cells. The parental cell prior to S-phase had five plasmids; the two daughter cells have only nine plasmids or four and one-half plasmids per cell. </p> </li> <li> <p> God JM, Haque A. <em>Burkitt lymphoma: pathogenesis and immune evasion.</em> (This work was supported by Grants from the National Institutes of Health) <i><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952908/?tool=pmcentrez" target="_blank" class="external">Oncol. 2010;2010. pii: 516047. </a></i> </p> <p> <img src="../IMG/Burkitt-lymphoma-defects-in-HLA-class-I-antigen-processing.jpg" alt="Defects in HLA class I antigen processing and presentation associated with BL." /></p> <p> <em>Defects in HLA class I antigen processing and presentation associated with BL.</em> Cytosolic proteins are ubiquitinated, marking them for proteasomal degradation. Peptides generated from proteasomal degradation are then transported into the endoplasmic reticulum (ER) lumen by TAP (transporter associated with Ag presentation) and loaded onto HLA class I proteins. These class I peptide complexes are transported through the Golgi network to the cell surface for presentation to CD8+ T cells. The EBV EBNA1 protein contains a Gly/Ala repeat that impairs its proteasomal processing, resulting in the generation of peptides that are not readily accessible to class I molecules. Thus, peptides generated from EBNA1 proteins are unable to activate CD8+ T cells in the context of HLA class I molecules. </p> <p> <img src="../IMG/Burkitt-lymphoma-defects-in-HLA-class-II-antigen-processing.jpg" alt="Defects in HLA class II antigen processing and presentation associated with BL. " /></p> <p> <em> Defects in HLA class II antigen processing and presentation associated with BL. </em> Extracellular Ags are endocytosed and degraded in increasingly acidified endolysosomal compartments. GILT helps in Ag/peptide processing by reducing disulfide bonds in the acidic environment. These peptides are further processed by acidic cathepsins for loading onto HLA class II proteins. HLA class II is synthesized in the ER lumen and forms a complex with Ii that is transported through the trans-Golgi network for processing by cathepsins in the endolysosomal compartments. Here Ii is degraded, leaving a fragment, CLIP, in the class II binding groove. HLA-DM mediates the release of CLIP and the loading of appropriate peptides onto HLA class II molecules. These complexes are then transported to the cell surface for presentation to CD4+ T cells. BL-associated inhibitory molecules (BLAIM) may interfere with functional class II presentation that perturbs CD4+ T cell recognition of BL. </p> <p> <img src="../IMG/Burkitt-lymphoma-and-B-lymphoblastoid-cell-line-comparison.jpg" alt="Comparison of BL and B-LCL highlighting the protein expression pattern of immune components that affects their abilities to stimulate CD4+ T cells." /></p> <p> <em> Comparison of BL and B-LCL highlighting the protein expression pattern of immune components that affects their abilities to stimulate CD4+ T cells. </em>BL cells normally express EBNA1, but not EBNA2 and LMP1. When compared to B-LCL, BL cells express higher levels c-myc, HLA-DO and BLAIM and lower levels of costimulatory molecules (CD80/86) that differentially regulate Ag processing and presentation, resulting in poor CD4+ T cell recognition of BL. </p> </li> <li><a class="external" target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=%22Epstein-Barr%20Virus%20Infections%22%5BMesh%5D%20AND%20%22Burkitt%20Lymphoma%22%5BMajr%5D&cmd=DetailsSearch"> "Epstein-Barr Virus Infections"[Mesh] AND "Burkitt Lymphoma"[Majr]</a></li> </ul> <div class="centered"> <script type="text/javascript"> ch_client = "nemose"; ch_width = 500; ch_height = 250; ch_type = "mpu"; ch_sid = "metapathogen"; ch_color_site_link = "#0000CC"; ch_color_title = "#0000CC"; ch_color_border = "#FFFFFF"; ch_color_text = "#000000"; ch_color_bg = "#FFFFFF"; </script> <script src="http://scripts.chitika.net/eminimalls/amm.js" type="text/javascript"> </script> <!--chitika AD--> </div> <div> <!-- Kontera ContentLink(TM);--> <script type='text/javascript'> var dc_AdLinkColor = 'blue' ; var dc_PublisherID = 79943 ; </script> <script type='text/javascript' src='http://kona.kontera.com/javascript/lib/KonaLibInline.js'> </script> <!-- Kontera ContentLink(TM) --> </div> <div class="centered"> <p> &nbsp;</p> <!--SPOTBACK--> <!-- get your own widget at http://spotback.com <script src='http://spotback.com/scripts/widgets/load.js?wid=48994'></script> <noscript> <a href="http://spotback.com" alt="Rate everything widget"> <img src="http://spotback.com/images/rating.gif" alt="user rating" /></a></noscript>--> <!--SPOTBACK--> <p> &nbsp;</p> </div> <div class="centered"> <p>&nbsp;</p> <!--letsgodynamic--><!-- div86544334647 --> <script type="text/javascript" src="http://letsgodynamic.com/sm-vidm/dispatcher/call.js.php?lang=EN&clientid=SCLNT018fed78ed96a284ed5414e265e37af2"></script><div id="div11873308574"><script type="text/javascript">request_send('SVIEWa8f93ba2d9c8d229dac066ac63b9e756','viewclientid=SCLNT018fed78ed96a284ed5414e265e37af2&globalid=11873308574','div11873308574','div11873308574');</script><a href="http://letsgodynamic.com">D-Modules: Comment service</a></div<!--letsgodynamic--> <p>&nbsp;</p> </div> <!-- <div> <p class="emphasis"> Please link to this page using the code in the text area. 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