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

Abstract

Summary 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 what 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 where 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.

High-throughput sequencing of the B-cell receptor in African Burkitt lymphoma reveals clues to pathogenesis

“…36 The consensus in the BL literature is that t(c-MYC;Ig) translocations occur in mature B cells due to recurrent antigenic stimulation and aberrant AID activity in the germinal center. [37][38][39][40] However, our data raise the possibility that the c-MYC translocation may actually occur in a developing B cell, before that cell completes DJ rearrangement on both IGH alleles, suggesting that BL precursors may emerge much earlier in B-cell development. Another group recently identified a pre-B-cell population with concurrent expression of recombination activating genes and AID, providing additional support for the possibility that the t(c-MYC;Ig) translocation could occur early in development.…”

Infection Exposure Is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result of Pax5-Inherited Susceptibility

“…The mechanisms responsible for the conversion of the preleukemic clone, carrying the inherited mutations of PAX5 , into pB-ALL are not understood yet. However, recent results suggest that the B-cell-specifi c enzyme AID is supposed to be the predominant driver of clonal evolution in human ETV6-RUNX1 pB-ALL ( 30-32 ) and B-cell lymphoma ( 33 ). These observations are in line with previous studies showing that AID is capable of initiating aberrant genomic alterations in precursor B cells ( 34 ) The pB-ALL that originated as a result of delayed infection exposure in Pax5 +/− mice offers a unique possibility to confi rm if the proposed mechanisms are involved in the conversion of the preleukemic clone into a full-blown leukemia ( 35,36 ).…”

Malaria-Induced B Cell Genomic Instability

“…Thus, an experimental system for B cell induction in a pathologically relevant infectious disease model has been lacking. In the Robbiani et al (2015) paper published in this issue of Cell, the laboratory of Michel Nussenzweig has linked B cell genome mutagenesis by AID to the real world problem of Plasmodium infection and its connection with endemic Burkitt lymphoma in equatorial Africa and New Guinea.…”