Burkitt's lymphoma: new insights into molecular pathogenesis (original) (raw)
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Burkitt's lymphoma in Africa, a review of the epidemiology and etiology
African health sciences, 2007
Burkitt's lymphoma (BL) was first described in Eastern Africa, initially thought to be a sarcoma of the jaw. Shortly it became well known that this was a distinct form of Non Hodgkin's lymphoma. The disease has given insight in all aspects of cancer research and care. Its peculiar epidemiology has led to the discovery of Epstein Barr virus (EBV) and its importance in the cause of several viral illnesses and malignancies. The highest incidence and mortality rates of BL are seen in Eastern Africa. BL affects mainly children, and boys are more susceptible than girls. Evidence for a causal relationship between EBV and BL in the endemic form is fairly strong. Frequency of association between EBV and BL varies between different patient groups and different parts of the world. EBV may play a role in the pathogenesis of BL by deregulation of the oncogene c-MYC by chromosomal translocation. Although several studies suggest an association between malaria and BL, there has never been a...
African Burkitt's lymphoma: a new perspective
Transactions of the Royal Society of Tropical Medicine and Hygiene, 2001
High titres of antibody to Epstein-Barr virus (EBV) late genes identify individuals at risk of developing endemic Burkitt's lymphoma (eBL). Vial lytic cycle early and intermediate-early gene expression in BL is associated with a favourable tumour response to chemotherapy. Our study investigated whether serological data identifying antibody expression to zta, a viral function that activates lytic-cycle gene expression, correlate with expression of its gene in turnours, and couid have prognostic value. Studies on 10 Malawian patients, with presumed BL on clinical grounds, showed good correlations, suggesting that serum antibody responses might predict treatment responsiveness. The results with 1 patient were particularly striking. When admitted in January 1998, prognosis was poor as he was unable to walk, and had tumour cells, characteristic of stage IV disease, in his bone marrow. Laboratory investigations showed particularly high levels both of serum ZEN antibodies and of gene expression in his tumour. Follow-up confirmed him alive 6 months after hospital discharge. Among the EBV-positive cases, 2 were ultimately diagnosed as rhabdomyosatcoma, a tumour not previously associated with this virus. The findings from this small study, if confirmed, should have value for future BL management in resource-poor parts of the world.
Distinctions between endemic and sporadic forms of epstein-barr virus-positive burkitt's lymphoma
International Journal of Cancer, 1985
Tumour cell lines were established in vitro from 16 cases of Epstein-Barr (EB) virus genome-positive Burkitt's lymphoma (BL), 7 of “endemic” origin (i.e. from holoendemic malarial areas of Africa and of New Guinea) and 9 of “sporadic” origin (i.e. from outside such high-incidence areas). All the BL cell lines thus established were monoclonal by immunoglobulin iso-type expression and displayed a characteristic chromosomal translocation, t(8:14) or t(8:22), confirming their malignant origin. Clear differences observed between the individual BL cell lines appeared to be related to their endemic or sporadic status. All 7 endemic cell lines began growth as a carpet of single cells, often with small, loose cumps appearing in later passage. Whilst 3 lines of sporadic origin displayed a similar pattern to the above, the majority of sporadic lines grew as large, tight clumps of cells from the first passage onwards. These differences in growth pattern were reflected by differences in cell surface phenotype, as defined in indirect immunofluorescence tests using a panel of monoclonal antibodies (MAbs) specific for B-lineage-associated antigens. BL cell lines could be classified into 3 separate groups on the basis of their reactivity with 6 particular antibodies (MHM6, AC2, Ki-1, Ki-24, J5 and 38.13). All 7 endemic BL cell lines and 2 of the 3 sporadic BL cell lines which began growth as single cells showed a group-I cell-surface phenotype (MHM6, AC2, Ki-1, Ki-24 negative; J5, 38.13 positive) in early passage. In contrast, all 6 sporadic BL cell lines which began growth in large clumps displayed a distinct group-11 phenotype (MHM6, AC2, Ki-1 positive/negative; Ki-24, J5, 38.13 positive); in later passage most of these sporadic lines progressed to a group-III phenotype (MHM6, AC2, Ki-1, Ki-24 positive; J5, 38.13 negative) without loss of those immunoglobulin and chromosomal markers identifying the cells' malignant origin. These clear differences between endemic BL cell lines on the one hand and the majority of sporadic BL cell lines on the other suggest that endemic BL arises from a more restricted range of progenitor B cells than does the sporadic form of the disease.
HIV: implication in Burkitt lymphoma
Biopolymers and Cell
Europe and in the US. This effect might be due to immune suppression and low CD4-cell counts associated with the development of AIDS. However, there is also evidence of a direct effect of HIV on B cell proliferation and differentiation, which may account for the development of B cell malignancies. We shall discuss possible mechanisms of implication of HIV in BL with a focus on the role of different viral components (Tat, Nef and gp120 proteins, viral envelope) in the c-myc/IgH translocation characteristic of BL.
Int J Cancer, 2002
Primary BL in Malawian children has a very high frequency association, approaching 100%, with the human herpesvirus EBV. A detailed study carried out on viral gene expression in these tumours, using both fresh material and methanol-fixed FNAs, showed, contrary to prediction, that most belong to a variant "class II" latency category, with lytic cycle-related genes also expressed. That is, in addition to EBNA1 expression, membrane proteins (LMP1/2A), immediate early (BZLF1) and early (IR2 and IR4) genes, a putative viral oncogene (BARF1), CST (BART) antisense transcripts and the viral bcl-2 homologue are expressed in a high proportion of the BLs. Most, but not all, express the small viral (EBER) RNAs. Two other significant observations were made: (i) in addition to expression of cellular cytokine (IL-10) transcripts in all tumours investigated, the normally silent viral IL-10 homologue was expressed in some tumours; (ii) whereas EBNA1 expression from its restricted Qp promoter was generally observed, the nonrestricted Cp/Wp promoter was also active in some tumours. Viral gene expression in the Malawian [endemic (e)] BLs appears to be more promiscuous than predicted from other studies, but expression accords with the cytopathologic picture of eBLs as a rapidly proliferating cell population accompanied by considerable necrosis, and a clinically diverse disease. A small-scale study of relapse Malawian BLs revealed a different picture of viral association, more akin to systemic BL than eBL, where EBV appears to be absent or present only at very low levels. The significance of these findings is considered.
The burden of Burkitt lymphoma in Africa
Infectious Agents and Cancer
Background: Burkitt lymphoma (BL) is a relatively common cancer of childhood in tropical Africa, although its precise incidence and continent-wide geographic distribution have not been previously systematically studied. Methods: Using the methods employed to produce national estimates of cancer incidence for the "Globocan" series of the International Agency for Research on Cancer, along with detailed information on cancer incidence by histological subtype from cancer registries in Africa, we estimate the numbers and rates of incidence by sex, age group, country and region of Africa. Results: We estimate that the number of new cases that occurred in 2018 to be about 3900, two thirds in males, and 81% in children aged 0-14. On a national basis, the geographic distribution of incidence rates among children in sub-Saharan Africa resembles that of the prevalence of infection with Falciparum malaria. An estimated 81% of cases are associated with infection with Epstein Barr virus (EBV). Conclusions: BL comprises almost 50% of childhood of non-Hodgkin lymphoma in Africa, almost all of which are associated with EBV, with the geographic distributionat least in sub Saharan Africa-mediated by infection with malaria.
Analysis of stepwise genetic changes in an AIDS-related Burkitt's lymphoma
International Journal of Cancer, 2000
In this study, immunoglobulin variable (Ig V) region genes, c-myc re-arrangement and sequence and p53 status were analyzed in clones derived from a Burkitt's lymphoma cell line (LAM) in which it was previously demonstrated that Epstein-Barr virus (EBV) infection occurred late during lymphomagenesis. Such evidence was based on the finding that 2 groups of cellular clones, characterized by the same c-myc re-arrangement but different EBV-fused termini, were obtained from the LAM cell line. The Ig V gene sequences were identical for the 2 groups of clones with different EBV-fused termini. The Ig variable heavy (V H ) gene sequence displayed a substantial accumulation of point mutations (but no intraclonal diversification), whereas the productive Ig V lambda (V ) gene sequence was virtually unmutated. Studies on the Ig V kappa (V ) locus suggested a receptor revision event (with a switch from to chain production) prior to EBV infection. Likewise, it was determined that the mutations observed in both p53 alleles and in the re-arranged c-myc gene occurred before EBV infection. Based on these findings, we present a model for the various steps of lymphomagenesis. It is proposed that stimulation by an antigen or a superantigen initially favored the clonal expansion and accumulation of other cytogenetic changes, including those involved in receptor editing. These events occurred prior to or during the germinal center (GC) phase of B-cell maturation. Thereafter, possibly upon exit of the cells from the GC, EBV infection occurred, further promoting lymphomagenesis. Int.