Abstract
Endemic Burkitt's lymphoma (eBL) arises from the germinal center (GC). It is a common tumor of young children in tropical Africa and its occurrence is closely linked geographically with the incidence of P. falciparum malaria. This association was noted more than 50 years ago. Since then we have learned that eBL contains the oncogenic herpes virus Epstein-Barr virus (EBV) and a defining translocation that activates the c-myc oncogene. However the link to malaria has never been explained. Here we provide evidence for a mechanism arising in the GC to explain this association. Accumulated evidence suggests that eBL arises in the GC when deregulated expression of AID (Activation-induced cytidine deaminase) causes a c-myc translocation in a cell latently infected with Epstein-Barr virus (EBV). Here we show that P. falciparum targets GC B cells via multiple pathways to increase the risk of eBL. 1. It causes deregulated expression of AID, thereby increasing the risk of a c-myc translocation. 2. It increases the number of B cells transiting the GC. 3. It dramatically increases the frequency of these cells that are infected with EBV and therefore protected from c-myc induced apoptosis. We propose that these activities combine synergistically to dramatically increase the incidence of eBL in individuals infected with malaria.
Highlights
Endemic Burkitt’s lymphoma is an extremely common tumor of young children in tropical Africa [1]
Since we have learned that Endemic Burkitt’s lymphoma (eBL) contains the oncogenic herpes virus Epstein-Barr virus and a defining translocation that activates the c-myc oncogene
We show that malaria has multiple effects that all focus on germinal center (GC) B cells that are known to be the origin of eBL
Summary
Endemic Burkitt’s lymphoma (eBL) is an extremely common tumor of young children in tropical Africa [1]. Phenotypic and transcriptional analysis suggests that it originates from germinal center (GC) cells [2,3] it grows in extrafollicular locations It is defined by a well described chromosomal translocation between the c-myc oncogene and one of the immunoglobulin loci that results in constitutive activation of the oncogene leading to uncontrolled growth of the cell [4,5,6]. AID is highly expressed in GC B cells and is normally responsible for the processes of somatic hypermutation and class switch recombination of immunoglobulin genes as they undergo affinity maturation in the GC [10]. This restricted expression of AID further supports the notion that eBL originates in the GC
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