A multifactorial role for P. falciparum malaria in endemic Burkitt's lymphoma pathogenesis
Charles Torgbor1, Peter Awuah2, Kirk Deitsch3
1Tufts University School of Medicine, Boston, Massachusetts, United States of America; Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology (KNUST) and Kumasi Centre for Collaborative Research, Kumasi, Ghana.
Insights
Malaria infection increases endemic Burkitt's lymphoma (eBL) risk by targeting germinal center B cells. This leads to deregulated AID expression, increased EBV infection, and c-myc activation, driving eBL development in children.
Area of Science:
- Immunology
- Oncology
- Infectious Diseases
Background:
- Endemic Burkitt's lymphoma (eBL) is a pediatric cancer prevalent in malaria-endemic regions.
- eBL is associated with Epstein-Barr virus (EBV) and c-myc oncogene activation.
- The etiological link between malaria and eBL remains unexplained.
Purpose of the Study:
- To elucidate the mechanism by which Plasmodium falciparum malaria contributes to eBL pathogenesis.
- To investigate the role of germinal center (GC) B cells in malaria-associated eBL.
Main Methods:
- The study focuses on the interplay between P. falciparum infection, GC B cell dynamics, EBV latency, and Activation-induced cytidine deaminase (AID) expression.
- Mechanistic insights are derived from accumulated evidence and proposed pathways.
Main Results:
- P. falciparum infection targets GC B cells, increasing deregulated AID expression and the risk of c-myc translocations.
- Malaria increases the number of B cells in the GC and the frequency of EBV-infected cells.
- EBV-infected cells are protected from c-myc-induced apoptosis, promoting oncogenesis.
Conclusions:
- P. falciparum malaria synergistically increases eBL incidence through multiple effects on GC B cells.
- This mechanism explains the geographical association between malaria and eBL.
- Targeting these pathways could offer novel strategies for eBL prevention or treatment.
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.
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