Genome destroyer identified in the immune system

Our bodies have such great capacity to heal, it’s hard to imagine that we naturally manufacture a product in our immune system that can endanger our own DNA and provide a biological footstep to cancer. But this is precisely the case. Researchers have found that a naturally occurring enzyme called activation-induced deaminase is a ”genome destroyer” that can initiate the DNA damage contributing to some B cell cancers, including Burkitt’s lymphoma.

From Rockefeller University :
”Genome destroyer” identified in the immune system

Enzyme called AID is the initial culprit in B cell cancers

Our bodies have such great capacity to heal, it’s hard to imagine that we naturally manufacture a product in our immune system that can endanger our own DNA and provide a biological footstep to cancer. But this is precisely the case.

In the August 20 issue of Cell, Michel Nussenzweig, Sherman Fairchild Professor and head of the Laboratory of Molecular Immunology, and his colleagues at The Rockefeller University, along with researchers at Weill Medical College of Cornell University, prove that a naturally occurring enzyme called activation-induced deaminase (AID) is a ”genome destroyer” that can initiate the DNA damage contributing to some B cell cancers, including Burkitt’s lymphoma.

As Nussenzweig explains, the publication ”pinpoints this enzyme as the one that causes the translocation,” a kind of chromosomal mutation, leading to transformation, or DNA damage at the cellular level. ”We’ve closed the circle on understanding how you get this class of cancer,” says Nussenzweig, who is a Howard Hughes Medical Institute investigator.

First author Almudena Ramiro, Ph.D., a postdoctoral associate from Madrid, explains the process: two frequent events in the immune system – class switch recombination and somatic hypermutation – contribute to the antibody diversity so important to immunity. Class switch recombination creates the different kinds of antibodies B cells generate for protecting the body from infection. Somatic hypermutation creates a higher affinity (essentially, a tighter fit) for antibodies doing their jobs of picking up antigens, or foreign material, in the body. AID is required to trigger both of them. In the absence of AID, such as in patients with a rare immune disorder called Hyper IgM type 2 syndrome, our ability to respond to infections is impaired. AID is therefore crucial to immune system function. Yet it also introduces an unseemly risk to the body.

”These two B cell processes were a little mysterious when I started working on this problem in 2001,” says Ramiro. ”Very little was known about AID except that it was involved, somehow, in class switch recombination and somatic hypermutation of B cells.” Now scientists know much more thanks to Ramiro and her colleagues’ efforts.

B cells perform a class switch recombination just once in their cellular lifespan. The AID enzyme turns on this activity. Once activated, by messages from immune system sentinel cells, for example, AID initiates breaks in the B cell’s DNA in order to trigger a recombination event to form antibodies with specialized functions. However, breakage of DNA can lead to translocations, where a piece from one chromosome becomes attached to a different chromosome. Out of the millions of base pairs that make up our genome, or DNA sequence present in every one of our cells, the B cell’s break and recombination process can unwittingly attack oncogenes, the genes that often contribute to cancer by ramping up or down cellular growth rates. Such a break in an oncogene could impair the genomic controls that keep it silent. ”There’s always a chance the B cell will render a DNA break in an oncogene. When B cells turn on AID, they roll the dice, in a big way,” says Nussenzweig.

For dozens of years, many immunologists thought that class switch recombination could contribute to the downside of B cell formation, namely lymphomas. But without causal evidence, as presented in the new Cell publication, AID as a genome destroyer was simply speculation.

Ramiro investigated the AID enzyme’s effects in a laboratory mouse strain, called IL-6 transgenic, which is prone to develop plasmacytomas, a type of B cell malignancy. In this research, she found an unusually high rate of translocations involving antibody genes and an oncogene called c-myc. Strikingly, these translocations are not present in the absence of AID. This finding indicates that translocations are a byproduct of AID function in class switch recombination. ”The frequency at which transformation occurs normally is very, very low because there are many factors preventing it at different stages,” says Ramiro. The class switch and somatic hypermutation processes have some built in controls, but they’re not foolproof. When many of the controls are removed, as they are in these genetically engineered mice, cancer is rampant. AID, uncontrolled, can become a body’s nemesis.

One set of controls may be other genes, known for their caretaking or gatekeeping abilities when DNA damage occurs.

”Both the class switching reaction and the somatic hypermutation reaction occur in phases, and for the translocation to occur, there has to be at least one mistake. The most likely place is the one initiated by AID, bringing together regions that are far apart in the chromosome, with one joining end being an oncogene,” says Nussenzweig. ”A caretaker gene would recognize and then fix an undesired break and repair; a gatekeeper would not let the B cell go through the cycle if it doesn’t take care of damage.”

Knowing now that AID can indeed induce chromosomal translocations, Nussenzweig and his colleagues would like to learn more about what is protecting the genome from these immune system-induced translocations under normal circumstances and how and when that protection fails.

AID is part of larger class of the body’s enzymes called the deaminases. Nussenzweig adds, ”it’s possible that in a larger sense this class of enzymes may initiate damage.” Knowing what we now know about the role of AID in the immune system may shed further light on general formation of cancers in the body.

For Ramiro and her colleagues, the questions of how AID is regulated remain open, and they want to learn more. ”We’re still at very basic research goals in understanding AID and what regulates it,” she says.

Funding for this research was provided by an initiative called a Specialized Center of Research (SCOR) grant from the Leukemia and Lymphoma Society. Selina Chen-Kiang, Ph.D., of Weill Cornell Medical College and a co-author of the Cell publication, is the principal investigator of the $7.5-million, multidisciplinary grant. In this unique institutional collaboration among Weill Cornell, Rockefeller University, and Sloan-Kettering, Nussenzweig studies the development and malignant transformation of plasma cells, while Chen-Kiang and others investigate how cell division and cell death control the generation of normal plasma cells and the development of myeloma. This SCOR grant for multiple myeloma is distinguished for being the first such grant in which a private, non-profit cancer organization earmarked for the study of blood cancers the kind of research dollars that had previously been primarily available only through the federal government.

The National Institutes of Health and the Ministerio de Educacion, Cultura y Deporte (Spain) also supported this research.


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