Research shows how the malária parasite increases risk of blood cancer
The mystery lasted half a century: work motivation was to find out how the two diseases are linked14/10/2015
A link between malaria and Burkitt lymphoma was described for the first time over 50 years ago, but how could a malaria infection increase the risk of cancer? After 50 years, researchers proved that DNA in mice B cells becomes vulnerable to cancer-causing mutations during prolonged combat to Plasmodium falciparum, the malaria-transmitting parasite.
Interviewed by the Brazilian Society of Tropical Medicine, a member of the staff in charge of the study, researcher Davide Robbiani, from the Rockfeller University (NY, USA), explains how the work was developed.
BSTM: What motivated the development of this study?
Davide Robbiani: Burkitt’s lymphoma is a cancer that mainly affects children and arises in B lymphocytes. Though it occurs worldwide, children living in malaria-endemic regions of equatorial Africa have a much higher risk (about ten times) of developing this particular type of lymphoma. The epidemiologic association between Plasmodium infection and Burkitt’s lymphoma has been known for more than half a century. However, there was little understanding about how the parasitic disease, which affects erythrocytes and hepatocytes, contributes to the development of a tumor of B lymphocytes. These immune cells are very important because they produce the antibodies that help fighting infections. One trigger to embark in this study was certainly the desire to provide new insights into a long-standing mystery of how the two diseases are connected.
BSTM: What approach did you use, and how long did the research take?
Davide Robbiani: To study the link between parasitic infection, genomic instability, and tumor development, we used Plasmodium chabaudi (Pc), which in mice causes a disease similar in many aspects to human malaria. Infection with Pc causes a marked and long-lasting expansion of activated B cells in the mouse spleen, and these cells express high levels of activation-induced cytidine deaminase (AID in short), a DNA mutating enzyme. AID is a very beneficial enzyme, as it remodels DNA at antibody genes during somatic hypermutation and isotype class switching, two reactions that are essential to produce highly potent antibodies that help neutralize the infection. However, AID is not a very precise enzyme. In addition to targeting antibody genes, it causes some collateral DNA damage, some of which occurs at cancer genes (such as the c-myc oncogene) that are rearranged in lymphoma. Thus, in a way, AID is a necessary risk: you need AID to make powerful antibodies, but the collateral genomic damage caused by AID can promote cancer. This has been an unusually long study (6+ years), as it required the refinement of previously existing techniques and the establishment of novel mouse models. This research would not have been possible without the support by several private foundations and by The Rockefeller University, in particular professor Michel Nussenzweig.
BSTM: How could you demonstrate that AID causes DNA mutations and B cell cancer during malaria infection?
Davide Robbiani: To document the genomic damage occurring in lymphocytes in vivo, we took advantage of a technique that we developed a few years ago and now further adapted for work in living organisms. This technique is called TC-seq (translocation-capture sequencing) and allows you to map, genome-wide, the DNA breaks that lead to chromosome rearrangements. By comparing translocations in AID proficient and AID deficient animals, we were able to establish that AID is responsible for a fraction of this damage. We then did a cancer experiment to test the role of AID in lymphoma development during malaria infection. First, we infected wild-type mice with Plasmodium, and no lymphoma developed. We then infected mice in whose B cells the p53 tumor suppressor gene had been deleted (p53 is commonly mutated in Burkitt’s lymphoma). In these mutant mice, we observed a striking phenotype: all AID proficient mice developed B cell lymphomas, which showed a mature phenotype and had chromosome translocations, similarly to Burkitt’s lymphoma in humans. In contrast, only about one third of AID deficient mice developed cancer. Based on this, we conclude that AID promotes mature lymphoma during malaria infection.
BSTM: What are the next steps? And can this work lead to novel treatments?
Davide Robbiani: Strategies aimed at limiting the collateral DNA damage inflicted by AID in chronically infected malaria patients would be useful. But first we need to understand how AID causes this detrimental damage, and this is an active area of research by many laboratories, including ours. Interestingly, lymphomas have been linked to other types of infection, and not just in Africa. For instance, people who suffer from chronic hepatitis C or have been infected by Helicobacter pylori have a higher incidence of non-Hodgkin lymphomas. It is possible that AID plays a role in the association between several types of infections and cancer.…