A link between malaria and Burkitt's lymphoma was first described more than 50 years ago, but how a parasitic infection could turn immune cells cancerous has remained a mystery. Now, in the August 13 issue of Cell, researchers demonstrate in mice that B cell DNA becomes vulnerable to cancer-causing mutations during prolonged combat against the malaria-causing Plasmodium falciparum.
Individuals who are chronically infected with certain pathogens are at increased risk of developing lymphomas, cancers of the antibody-producing B lymphocytes. For example, Burkitt's lymphoma, a common form of childhood cancer, is ten times more frequent in areas of equatorial Africa that are endemic for malaria. How the malaria-causing parasite promotes blood cell cancer was not known.
Davide Robbiani of The Rockefeller University and his colleagues decided to tackle this question by studying malaria infections in mice. They discovered that during prolonged immune responses to malaria, B lymphocytes multiply extensively and show prolonged expression of an enzyme called AID (activation-induced cytidine deaminase). Normally, AID mutates DNA at antibody genes to promote shuffling of DNA, which generates the diversity of antibodies so crucial for combating infections. However, Robbiani's team found that in malaria-infected B lymphocytes, AID instead wreaks widespread havoc, causing DNA rearrangements at other genes, including those involved in the development of cancer.
"Thus AID is a necessary risk: you need AID to make potent antibodies to fight infection, but AID also causes collateral damage, leading to DNA breaks and mutations, thus increasing the odds of cancer," Robbiani says.
Robbiani notes that hepatitis C virus and Helicobacter pylori infections, as well as some autoimmune diseases, are also linked with chronic B lymphocyte activation and an increased risk of lymphoma. Therefore, strategies aimed at reducing unintended DNA damage caused by AID might also help reduce the risk of lymphoma in patients affected by these conditions.
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This work was supported by the Worldwide Cancer Research (formerly known as Association for International Cancer Research), the Fondazione Ettore e Valeria Rossi, and the National Institutes of Health.
Cell, Robbiani et al.: "Plasmodium Infection Promotes Genomic Instability and AID-Dependent B Cell Lymphoma" http://dx.doi.org/10.1016/j.cell.2015.07.019
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