Plasmodium Infection Promotes Genomic Instability and AID-Dependent B Cell Lymphoma

Chronic infection with Plasmodium falciparum was epidemiologically associated with endemic Burkitt’s lymphoma, a mature B cell cancer characterized by chromosome translocation between the c-myc oncogene and Igh, over 50 years ago. Whether infection promotes B cell lymphoma, and if so by which mechanism, remains unknown. To investigate the relationship between parasitic disease and lymphomagenesis, we used Plasmodium chabaudi (Pc) to produce chronic malaria infection in mice. Pc induces prolonged expansion of germinal centers (GCs), unique compartments in which B cells undergo rapid clonal expansion and express activation-induced cytidine deaminase (AID), a DNA mutator. GC B cells elicited during Pc infection suffer widespread DNA damage, leading to chromosome translocations. Although infection does not change the overall rate, it modifies lymphomagenesis to favor mature B cell lymphomas that are AID dependent and show chromosome translocations. Thus, malaria infection favors mature B cell cancers by eliciting protracted AID expression in GC B cells. [Display omitted] [Display omitted] •Capture of chromosome translocations occurring in germinal center B cells in vivo•AID promotes Plasmodium-associated B cell lymphoma•Chronic infection causes a shift toward a more mature lymphoma phenotype•Plasmodium-induced lymphomas bear chromosome translocations, including c-myc/Igh Chronic infection with Plasmodium parasites induces widespread genomic instability and favors mature B cell cancers by eliciting protracted AID expression in GC B cells, explaining the association between malaria and development of Burkitt’s lymphoma.