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Burkitt lymphoma (BL) is an aggressive B-cell malignancy with endemic, sporadic and immunodeficiency-associated variants. It has been known for many years that the fundamental transforming event in BL is the translocation of the MYC gene, and the events that bring about this translocation and those that allow cells to survive with the constitutive expression of MYC have been the subject of intense investigation. Epstein-Barr virus (EBV) infection, malaria, immunodeficiency and spontaneous, somatic mutation can all contribute to the origin and maintenance of this cancer and their mechanisms are the subject of this review.
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PMID:Epstein-Barr virus and Burkitt lymphoma. 1804 96

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 conclusive population study in support of a direct role of malaria in causation of BL. The emergence of HIV and a distinct subtype of BL in HIV infected have brought a new dimension to the disease particularly in areas where both HIV and BL are endemic. BL has been reported as a common neoplasmin HIV infected patients, but not in other forms of immuno-depression, and the occurrence of BL seems to be higher amongst HIV positive adults, while the evidence of an association amongst children is still disputed. The role of other possible risk factors such as low socio-economical status, exposure to a plant species common in Africa called Euphorbiaceae, exposure to pesticies and to other infections such as schistosomiasis and arbovirus (an RNA virus transmitted by insect vectors) remain to be elucidated.
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PMID:Burkitt's lymphoma in Africa, a review of the epidemiology and etiology. 1805 71

Differing trajectories of infant and child growth are associated with different patterns of disease and mortality in adulthood. Since postnatal growth patterns are partially modifiable by diet, these associations raise fresh questions about what constitutes an optimal growth rate. We use data from contemporary societies that still suffer poor nutrition and high burdens of infectious disease to illustrate early growth patterns that have likely been typical of our evolutionary past. Pathogenic assault is a major suppressor of growth; populations frequently average -1.0 to -1.5 z scores (standard deviations relative to standard growth curves) for height, and -2.0 to -2.5 z scores for weight, body mass index and head circumference. Many infections are symptomatic (e.g. diarrhea, malaria, pneumonia, HIV), but others are subclinical (e.g. hepatitis B, cytomegalovirus, Epstein-Barr virus, herpes, Helicobacter pylori). The great majority of young children become infected by multiple pathogens which initiate a downward cycle of infection --> suppressed appetite and malabsorption --> reduced growth --> lowered immunity --> repeated infection. Examination of the evolutionary 'norm' for early growth, and the external environmental factors that influenced it, may provide clues towards identifying the current day optimum for growth.
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PMID:Growth and host-pathogen interactions. 1819 53

We reviewed the scientific literature on Burkitt's lymphoma (BL) in Africa in order to provide information on the current status of clinical care and the existing research challenges. BL epidemiology led to the discovery of the Epstein Barr virus, an important cause of several viral illnesses and malignancies. The incidence of BL has increased in the endemic areas of Africa, overlapping with the epidemic of HIV and increase of malaria. The impact of this on the clinical care of BL in the region is therefore of interest, especially in HIV-infected children. Rapid methods must be developed which enable the correct diagnosis to be made. It is important to improve supportive care to allow fairly aggressive treatment, to research into salvage therapy for those who fail first-line treatment, and to develop less toxic drug combinations for HIV-infected patients. Documentation of HIV status through counselling should be offered to all patients.
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PMID:Current investigations and treatment of Burkitt's lymphoma in Africa. 1830 50

Traditional Chinese medicine commands a unique position among all traditional medicines because of its 5000 years of history. Our own interest in natural products from traditional Chinese medicine was triggered in the 1990s, by artemisinin-type sesquiterpene lactones from Artemisia annua L. As demonstrated in recent years, this class of compounds has activity against malaria, cancer cells, and schistosomiasis. Interestingly, the bioactivity of artemisinin and its semisynthetic derivative artesunate is even broader and includes the inhibition of certain viruses, such as human cytomegalovirus and other members of the Herpesviridae family (e.g., herpes simplex virus type 1 and Epstein-Barr virus), hepatitis B virus, hepatitis C virus, and bovine viral diarrhea virus. Analysis of the complete profile of the pharmacological activities and molecular modes of action of artemisinin and artesunate and their performance in clinical trials will further elucidate the full antimicrobial potential of these versatile pharmacological tools from nature.
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PMID:The antiviral activities of artemisinin and artesunate. 1869 44

Burkitt lymphoma (BL) is an aggressive B-cell malignancy with endemic, sporadic and immunodeficiency-associated variants. It has been known for many years that the fundamental transforming event in BL is the translocation of the MYC gene, and the events that bring about this translocation and those that allow cells to survive with the constitutive expression of MYC have been the subject of intense investigation. Epstein-Barr virus (EBV) infection, malaria, immunodeficiency and spontaneous, somatic mutation can all contribute to the origin and maintenance of this cancer and their mechanisms are the subject of this review.
 ...
PMID:Epstein-Barr virus and Burkitt lymphoma. 1871 17

Burkitt's lymphoma (BL) was first described 50 years ago, and the first human tumour virus Epstein-Barr virus (EBV) was discovered in BL tumours soon after. Since then, the role of EBV in the development of BL has become more and more enigmatic. Only recently have we finally begun to understand, at the cellular and molecular levels, the complex and interesting interaction of EBV with B cells that creates a predisposition for the development of BL. Here, we discuss the intertwined histories of EBV and BL and their relationship to the cofactors in BL pathogenesis: malaria and the MYC translocation.
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PMID:The curious case of the tumour virus: 50 years of Burkitt's lymphoma. 1900 91

Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in equatorial Africa and is linked to Epstein-Barr virus (EBV) and Plasmodium falciparum coinfections early in life. Epstein-Barr nuclear antigen 1 (EBNA1) is the sole viral latent antigen expressed in BL tumors. Loss of EBNA1-specific immune surveillance could allow eBL emergence. Therefore, EBNA1-specific T cell responses were analyzed by IFN-gamma ELISPOT in Kenyan children with eBL and compared to healthy children with divergent malaria exposure. Significantly fewer children with eBL, 16% (7/44) had EBNA1-specific IFN-gamma responses in contrast to healthy children living in a malaria holoendemic area or in an area with sporadic malaria transmission, 67% (40/60) and 72% (43/60) responders, respectively (p < 0.003). Children with eBL maintained IgG(1) dominated antibody responses to EBNA1 similar to healthy children suggesting a selective loss of IFN-gamma secreting EBNA1-specific T cells in the presence of intact humoral immunity. CD8(+) T cell responses to EBV lytic and latent antigens not expressed in the tumors were similarly robust in eBL patients compared to healthy children. In addition, CD4(+) T cell responses to a malaria protein, merozoite surface protein 1, were present in lymphoma patients. This study demonstrates a selective loss of EBNA1-specific T cell responses in children with eBL and suggests a potential immunotherapeutic target for this EBV-associated lymphoma.
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PMID:Children with endemic Burkitt lymphoma are deficient in EBNA1-specific IFN-gamma T cell responses. 1908 27

To study the long term the effects of chronic exposure to P. falciparum malaria on Epstein-Barr virus (EBV) reactivation in children, EBV-specific antibody levels were measured in a cross-sectional survey of two groups of Kenyan children with divergent malaria exposure, varying in age from 1 to 14 years. A total of 169 children were analyzed within three age groups (1-4 years, 5-9 years and 10-14 years). Using a Luminex assay, elevated levels of IgG to EBV lytic and latent antigens were observed in children from the holoendemic malaria area; these remained elevated for each age group studied. In comparison, children from the sporadic malaria area had lower levels of EBV-specific IgG antibodies and these levels declined across age groups. These data suggest that chronic exposure to malaria may lead to long-term EBV reactivation.
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PMID:Serological evidence for long-term Epstein-Barr virus reactivation in children living in a holoendemic malaria region of Kenya. 1938 56

Chromosomal translocations that juxtapose one of the three immunoglobulin loci to the c-myc protooncogene are the hallmark of Burkitt lymphomas (BLs), whether they carry the Epstein Barr Virus (EBV) or not. Ig/myc translocations occur as accidents of normal B lymphocyte differentiation. Unless protected, the translocation carrying cells are apoptosis prone. However, the high B cell stimulatory cytokine level found in the two BL prone conditions, in chronic hyperendemic malaria and HIV infection, may rescue them. X-linked lymphoproliferative disease (XLP) is due to the lack of functional SAP protein, a consequence of mutation or deletion of the SAP gene. We and others have shown that SAP is pro-apoptotic. Here we summarize our finding that 8 of 10 EBV carrying, but none of 9 EBV negative BL lines express SAP. We suggest that the apoptosis prone Ig/myc translocation carrying EBV negative precursors of BL can only grow into lymphomas if they do not express SAP. However, their EBV positive counterparts are permissive for SAP expression, due to the anti-apoptotic function of EBNA-1.
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PMID:To the genesis of Burkitt lymphoma: regulation of apoptosis by EBNA-1 and SAP may determine the fate of Ig-myc translocation carrying B lymphocytes. 1987 94


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