Enzyme may hold key to B Cell lymphomas
Scientists have long understood AID's crucial role in the adaptive immune system, which is responsible for managing the body's responses against pathogens. The gene ensures that B cells — the cells responsible for antibody production — can mutate their genome, generating antibodies that can mount more effective immune responses. A chemical reaction that affects the behavior of a gene crucial to the body's defense against pathogens mobilizes immune cells to effectively fight the invaders, a team led by scientists at Weill Cornell Medical College discovered in a new study. Their findings are the first to demonstrate an epigenetic role for the gene, activation-induced cytidine deaminase (AID), and may reveal a potential cause of blood cancers.
Now, the Weill Cornell researchers have discovered a new role for the gene. In their study, published online Sept. 10 and in the Sept. 29 issue of Cell Reports, the researchers discovered that the enzyme encoded by the AID gene is also involved in removing chemical tags from DNA. These tags, known as methyl groups, regulate gene expression. Removing these methyl groups, a process called hypomethylation, allows B cells to rapidly change their genome in preparation for antibody production.
"AID is a gene traditionally not known to be linked to DNA methylation, but we found that it is a player in removing methyl groups — the first time anyone has found molecules that perform this powerful form of gene regulation," said co-senior author Dr. Olivier Elemento, an associate professor of computational genomics in the Department of Physiology and Biophysics who heads the Laboratory of Cancer Systems Biology in the Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine at Weill Cornell and co-chairs the Meyer Cancer Center Program in Genetics, Epigenetics and Systems Biology. "What is interesting is that many tumor types, and that includes B-cell lymphomas, tend to be linked to global — genome-wide — hypomethylation, compared to normal cells. How hypomethylation occurs is not well understood. AID is so far the only enzyme that has been directly linked to this active process. So AID or related enzymes could be involved in other cancers as well."
The researchers also found that the enzyme may increase epigenetic diversity — the extent to which each cell has a distinct pattern of chemical tags attached to DNA. Epigenetic diversification may promote the production of more diversified antibodies but may also contribute to the development of cancers such as non-Hodgkin lymphoma, chronic lymphocytic leukemia and diffuse large B-cell lymphoma, among others. This may happen because once a methyl group is removed from a gene, it is not put back on, "raising the risk that epigenetic alterations can turn on other pathways that cause the cells to grow out of control," Dr. Elemento said. "A lot of potentially dangerous processes occur during this sensitive stage, and while much of it is tightly controlled, some may get out of control."
Understanding AID's epigenetic role could lead to new strategies to treat these cancers, which affect some 100,000 Americans a year, the researchers said.
"Our animal models lead us to believe that expression of AID and epigenetic changes do contribute to cancer, making disease more aggressive. This is something we are investigating now," says co-senior author Dr. Rita Shaknovich, a former Weill Cornell Medical College researcher now working with Cancer Genetics Inc., a global cancer diagnostic biotech company. "No drugs that we know of now could target AID, but we are becoming more and more sophisticated in creating targeted therapies, and so it is feasible that we could base a future treatment that disables AID in a specific way."