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Recent investigations indicate that Burkitt's lymphoma consists of several subtypes, defined by their clinical and molecular features. Each geographical region so far studied appears to consist of a different mixture of subtypes. Interestingly, there appear to be geographic 'gradients' with respect to the fraction of tumors associated with EBV and the type of 8;14 chromosomal translocation. The rate of EBV association is highest in Equatorial Africa, lowest in North America and intermediate in South America. The fraction of tumors with breakpoints far upstream of the c-myc gene follows a similar pattern. These findings strongly suggest that the subtypes of Burkitt's lymphoma are environmentally determined, and we propose that the pattern of infection (e.g. malaria) to which the young child is exposed influences the tumor subtype distribution by altering the relative and absolute numbers of various B cell precursors at sites of B cell ontogeny (the bone marrow, and possibly mesentery). These B cell precursors are the cells which are susceptible to the specific chromosomal translocations associated with Burkitt's lymphoma. We further propose that immunoglobulin enhancers (recognized and unrecognized) both influence the likelihood of the translocation occurring, and in at least a fraction of cases, contribute to the deregulation of a c-myc. EBV, via EBNA-1, the only invariably expressed latent-gene in Burkitt's lymphoma, probably influences c-myc expression in Burkitt's lymphoma by increasing immunoglobulin enhancer function. Thus, in effect, EBV collaborates with the translocations associated with Burkitt's lymphoma in causing c-myc deregulation. This collaboration is independent of the breakpoint location. While other molecular abnormalities must be able to contribute to myc deregulation in the same way, EBV association in Burkitt's lymphoma is probably determined by the age at which EBV infection occurs (being more likely when infection occurs in very young children) and perhaps also by other infectious diseases that numerically influence the fraction, and predominant stage of differentiation (and hence translocation breakpoint sites) of immature B cells infected by EBV. The presence of EBV in many such cells greatly increases the incidence rate of Burkitt's lymphoma, since one of the genetic lesions needed to deregulate c-myc is already present.
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PMID:Epstein-Barr virus and Burkitt's lymphoma. 133 92

The function of c-myc in physiology is only partially known. Its product has DNA binding properties and plays a role in the control of proliferation and differentiation. In general, increased c-myc expression leads to proliferation and abolishment of differentiation. The involvement of c-myc in mouse plasmacytomas and human Burkitt's lymphoma is well known: due to chromosomal translocation c-myc comes under the influence of regulatory elements of immunoglobulin genes, leading to increased expression of the gene and proliferation of the cells. In man, the chromosomal translocations may occur within the increased pool of (pre) B-cells due to Epstein Barr virus (EBV) and malaria infection with subsequent immunosuppression. Apart from these early (primary?) events in lymphomagenesis, c-myc is also often involved in tumour progression, probably by a similar mechanism. Different types of c-myc involvement are associated with specific types of lymphoma: there are differences between endemic, sporadic and ileocecal Burkitt's lymphoma as well as between those and primary extranodal large cell lymphoma and large cell lymphoma which has progressed. These differences are associated with the differentiation of the involved lymphoid cells and may point to the stage of differentiation in which the oncogenic event occurred.
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PMID:The association of c-myc rearrangements with specific types of human non-Hodgkin's lymphomas. 149 39

Burkitt's lymphoma (BL) is a highly malignant B cell tumor characterized by three types of chromosomal translocation which constitutively activate the c-myc oncogene by juxtaposing it to Ig coding sequences. Epstein-Barr virus (EBV) infection, hyperendemic malaria and HIV-caused immunosuppression are thought to contribute to the pathogenesis of the tumor. Cell lines derived from EBV carrying and EBV negative BLs often show altered MHC class I antigen expression. The defects include a lower expression of all HLA class I antigens compared to EBV transformed normal B-blasts, and selective down-regulation of certain HLA-A and HLA-C alleles. As a consequence BL cells are often resistant to cytotoxic T lymphocyte (CTL) mediated destruction. Alleles selective down-regulations are found only in cell lines that maintain the tumor cell phenotype while shift towards a more activated 'B-blast like' phenotype is accompanied by HLA class I up-regulation. A similar pattern of HLA class I expression can be found in a subpopulation of germinal center B cells which express a 'BL like' phenotype. Our findings suggest that the HLA class I expression of BL cells reflects the characteristics of the normal B cell precursor and is probably not the result of immune selection.
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PMID:Cell phenotype dependent expression of MHC class I antigens in Burkitt's lymphoma cell lines. 165 15

Burkitt's lymphoma is the most common childhood cancer in Africa. Most prevalent in areas endemic for malaria, the disease, a malignant growth of lymphoid tissue, usually presents itself as a large tumour of the jaw. When first characterized in the 1950s, the lymphoma was thought to spread by some infectious agent. Subsequent research indicates that the frequent involvement of an infectious agent is but one factor in a more complex aetiology. Today, Burkitt's lymphoma is considered an example of multistep carcinogenesis. Each step in the process results from a different agent. The agent in the first step is the Epstein-Barr virus, which infects B cells of the immune system causing a proliferation of these cells. The second step, malarial infection, furthers the proliferation of B cells providing a large population of cells available for a chromosomal translocation which represents the third step in the formation of the lymphoma. The chromosomal translocation places a cancer causing gene, c-myc, in close proximity to an active antibody-encoding its proliferation resulting in a cell capable of unlimited growth which serves as the nucleus of a B cell lymphoma.
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PMID:Burkitt's lymphoma and the role of Epstein-Barr virus. 216 60

Burkitt's lymphoma is characterized by particular epidemiological features. It is a frequent childhood tumor in children in tropical Africa and occurs at a much lesser frequency all over the world. Chromosomal translocation affecting the long arm of chromosome 8 (band 8q24) and one of the chromosomes carrying the immunoglobulin loci (chromosomes 2, 14 or 22) are regularly observed in Burkitt's lymphoma, regardless of whether the tumor occurred in high or low incidence areas. The prevalence of Burkitt's lymphoma in Africa appears to be related to two factors: holo- or hyperendemic malaria and presence of Epstein-Barr virus genomes in the tumor cells. We present a model of pathogenesis, in which stimulation of B cells by malaria is the primary event in the development of the disease. The risk of the chromosomal translocation should be increased by increasing the number of new B cells generated per time. According to our model, the translocation leads to constitutive c-myc activation and makes the cells responsive to growth factors without inducing proliferation on its own. Infection of a translocation-carrying cell with EBV may provide an additional growth advantage and drive the cell further towards a fully malignant state.
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PMID:[Chromosome translocations and Epstein-Barr virus in Burkitt's lymphoma]. 282 99

The recognition of Burkitt lymphoma (BL) as a clinical syndrome and a pathological entity in African children resulted from astute clinical observations (bedside epidemiology), the availability of cancer registry data and accurate pathological interpretation. Following the early studies in Africa, it soon became evident that this tumor occurred worldwide and the excess of cases in Africa was an incidence phenomenon associated with specific environmental factors. The sentinel discovery of the Epstein Barr virus (EBV) and its association with BL stimulated a wide variety of scientific investigations which have had an impact of virtually every discipline and biology. Epidemiological observations linked to modern laboratory techniques have provided etiological insights which implicate specific environmental factors and genetic events in the pathogenesis of BL and other immunoproliferative diseases. Early infection with EBV and holoendemic malaria are clearly of paramount importance in the development of endemic BL (eBL). These factors do not play a role in the majority of sporadic BL (sBL) cases, but immunosuppression and T-cell deregulation almost certainly are common denominators. The final or principle genetic event in both instances would appear to be the chromosome 8 translocation involving the c-myc oncogene and structural alteration. It is expected that the BL model will continue to be a useful one for identifying basic mechanisms in carcinogenesis which may be applicable as well to a variety of non-neoplastic diseases.
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PMID:Malignant lymphoma in African children: three decades of discovery. 285 87

The Epstein-Barr virus (EBV), a B lymphotropic virus, is involved in a growing number of immunopathological disorders benign or malignant. The X-linked lymphoproliferative syndrome and its multifaceted clinical expression in a unique situation described in this issue by Purtilo. Among recent findings, the association between EBV and idiopathic interstitial pneumopathy (also named cryptogenic fibrosing alveolitis), is to be noted (6). From a molecular biology view-point, in vitro immortalization of B lymphocytes by EBV is under a pluri-genic (EBNA 2, EBNA 1, LYDMA) control. The role of EBV in oncogenesis appears different in Burkitt's Lymphoma (BL) and in nasopharyngeal carcinoma (NPC). In development of African BL, EBV appears to initiate the multistage carcinogenic event, through an early and massive infection. Other events include specific depression of T-cell immunity by hyperendemic malaria and c-myc onc-gene activation through chromosome translocation. In the genesis of NPC, the role of EBV still remain to be clarified although the strong and consistent association between EBV and the undifferentiated carcinoma of the nasopharyngeal (NPC) around the world favours an etiological relationship. The simple detection of IgA antibodies to VCA and EA allows early detection of the NPC, thus permitting a 95% cure rate at 5 years post-radiotherapy. Such an early diagnostic is of paramount public health importance. Furthermore, IgA/VCA and IgA/EA antibodies characterize precancerous conditions, giving the theoretical possibility of preventive interventions.
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PMID:The Epstein-Barr virus (EBV): a Rosetta Stone for understanding the role of viruses in immunopathological disorders and in human carcinogenesis. 299 May 89

Endemic Burkitt's lymphoma, a tumour of children in which B lymphocytes are infected with Epstein-Barr virus (EBV), is common in areas of Africa where malaria is holoendemic. The tumour is characterized by chromosome translocations; usually the terminal portion of chromosome 8 containing the c-myc gene is translocated to chromosome 14, near the enhancer of the immunoglobulin heavy-chain locus. Less frequent are translocations of chromosome 8 to the kappa light-chain locus of chromosome 2 or to the lambda light-chain locus of chromosome 22. In vitro, EBV induces B cells to proliferate and secrete immunoglobulin and antibody. However, in vivo the infected B lymphocytes are under immunological control, so that abnormal proliferation is found only in immunosuppressed patients. Such patients are subsequently liable to develop lymphomas. Burkitt believed that the tumour he had described resulted from interaction between a virus(es) and a "reticuloendothelial system altered by chronic and heavy infection by malarial or other parasites". We report here that during an attack of Plasmodium falciparum malaria, T-cell subpopulations are radically altered so that, in vitro, B lymphocytes infected with EBV proliferate abnormally to secrete large amounts of immunoglobulin and antibody. This phenomenon offers some explanation for the increased incidence of Burkitt's tumour and the high levels of immunoglobulin found in people living in areas where P. falciparum malaria is common.
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PMID:T-cell control of Epstein-Barr virus-infected B cells is lost during P. falciparum malaria. 609 4

The etiology of Burkitt's lymphoma (BL) includes three factors which operate in a stepwise fashion: (1) the ubiquitous Epstein-Barr virus (EBV) which possesses oncogenic potential when it infects infants or very young children; (2) malaria which specifically depresses cytotoxic T cell clones controlling the polyclonal proliferation of EBV-infected B cells in the host; and (3) chromosomal translocations activating the c-myc oncogene which in turn induces uncontrolled B cell proliferation. The unravelling of such a multistep carcinogenic process has shaken a number of well-established dogmas of our time.
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PMID:The etiology of Burkitt's lymphoma and the history of the shaken dogmas. 801 47

At least three genetic changes are known to contribute to the genesis of Burkitt's lymphoma (BL): the Ig/myc translocation, the presence of Epstein-Barr virus (EBV) in the vast majority of the endemic and a minority of sporadic tumors, and a p53 mutation, present in approximately 60% of the BL-derived lines. Activation of c-myc by juxtaposition to Ig sequences is a universal common denominator in endemic and sporadic EBV positive and negative BLs. It acts by preventing the cell from leaving the cycling compartment and by facilitating immune escape. EBV probably acts by expanding the target cell population at risk and prolonging its life span. This, together with the malaria co-factor, would increase the risk of the translocation accident. The p53 mutation may be essential for the continued growth of the tumors where it occurs, since introduction of wild-type p53 leads to their apoptotic death.
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PMID:Multistep evolution of B-cell-derived tumors in humans and rodents. 827 58


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