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Malaria-Causing Parasite May Contribute to Development of Burkitt Lymphoma

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Key Points

  • Researchers infected mice with Plasmodium chabaudi and immediately saw an increase in germinal-center B lymphocytes, the activated form of the white blood cells that can give rise to Burkitt lymphoma.
  • As these cells rapidly proliferate, they also express high levels of an enzyme known as activation-induced cytidine deaminase (AID), which induces mutations in their DNA.
  • The researchers found that all mice that expressed AID but not p53, which is known to protect organisms from many kinds of cancer, developed lymphoma.

In an equatorial African region known as the “lymphoma belt,” children are ten times more likely than in other parts of the world to develop Burkitt lymphoma. This area is also plagued by high rates of malaria, and scientists have spent the past 50 years trying to understand how the two diseases are connected. The link has been a mystery: The parasite that causes malaria infects red blood cells and liver cells, whereas Burkitt lymphoma originates in B lymphocytes. So how could a malaria infection increase a child's risk of developing this type of cancer?

A team of Rockefeller University researchers led by Michel Nussenzweig, MD, PhD, the Zanvil A. Cohn and Ralph M. Steinman Professor and Head of the Laboratory of Molecular Immunology, has helped explain why. Working with mice, they found that the same enzyme that helps create antibodies that fight off the malaria parasite also causes DNA damage that can lead to Burkitt lymphoma. The research was published by Robbiani et al in Cell.

“I think of this process as a necessary risk,” said Davide Robbiani, MD, PhD, Research Associate Professor in Dr. Nussenzweig's laboratory. “The body needs this enzyme in order to produce potent antibodies to fight malaria. But in the process, the enzyme can cause substantial collateral damage to the cells that produce it, and that can lead to lymphoma,” he added.

Study Details

In the study, the researchers infected mice with a form of the parasite that causes malaria, Plasmodium chabaudi. They immediately saw that the mice experienced a huge increase in germinal-center B lymphocytes, the activated form of the white blood cells that can give rise to Burkitt lymphoma. “In malaria-infected mice, these cells divide very rapidly over the course of months,” said Dr. Robbiani.

As these cells rapidly proliferate, they also express high levels of an enzyme known as activation-induced cytidine deaminase (AID), which induces mutations in their DNA. As a result, these cells can diversify to generate a wide range of antibodies. But in addition to beneficial mutations in antibody genes, said Dr. Robbiani, AID can cause “off-target” damage and shuffling of cancer-causing genes. “In mice infected with the malaria parasite, these so-called chromosomal rearrangements occur very frequently in germinal-center lymphocytes,” said Dr. Robbiani, “and at least some of the changes are due to AID.”

Next, the researchers bred mice lacking the p53 gene, which is known to protect cells from many types of cancer, including Burkitt lymphoma. In analyzing mice that expressed AID but not p53, they found that every single one developed lymphoma. When these mice were infected with the malaria parasite, they developed lymphomas specifically in mature B cells, similarly to what happens in Burkitt lymphoma. “This finding sheds new light on a long-standing mystery of why two seemingly different diseases are associated with each other,” said Dr. Robbiani.

Next Steps

Groups at Rockefeller and elsewhere are trying to understand how AID causes its off-target damage to DNA, which could lead to new treatments. “If we could somehow limit this collateral damage to cancer-causing genes without reducing the infection-fighting powers of B cells, that could be very useful,” he said. “But first, we have to find out how the collateral DNA damage occurs in the first place.”

There are no additional cancers associated with malaria, but lymphomas have been linked to other types of infections, and not just in Africa, said Dr. Robbiani. For instance, people with hepatitis C or the ulcer-causing bacterium Helicobacter pylori have a higher incidence of non-Hodgkin lymphomas, he noted. “It's possible that AID also plays a role in the association between these other infections and cancer.”

Drs. Nussenzweig and Robbiani are the corresponding authors of the Cell article.

This study was supported by Worldwide Cancer Research, the Fondazione Ettore e Valeria Rossi, and U.S. federal grants.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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