New Target for Non-Hodgkin's Lymphoma
Targeting the uracil-DNA glycosylase enzyme may help treat certain types of non-Hodgkinâ€™s lymphoma.
New findings revealed that the enzyme uracil-DNA glycosylase (UNG) protects the ends of B cell chromosomes that contain telomeres in order to facilitate the proliferation of the activated B cells in response to infection. However, in the absence of UNG, these telomeres become lost.
When foreign antigens are first presented to a B cell, the B cell will begin to proliferate to produce a DNA modifying enzyme called activation-induced deaminase (AID). AID creates mutations in the cell’s immunoglobulin genes so that the cell’s progeny produce a diverse range of antibodies that are able to bind to the antigen with high affinity and mediate various immune responses.
However, AID can also create mutations in other areas of the B cell’s genome. If UNG or other DNA repair proteins do not mend these mutations, it can lead to cancers such as non-Hodgkin’s lymphoma. In a new study, a research team chose to investigate whether or not AID targets the telomeres of mouse B cells, since telomeres contain similar DNA sequences to immunoglobulin genes.
The results of a study published in The Journal of Experimental Medicine showed that when UNG was absent, AID created mutations in B cell telomeres, which caused them to rapidly shorten and limited the proliferation of activated B cells. The UNG enzyme helped to repair the mutations, therefore preventing telomere loss and facilitating B cell expansion.
The findings indicate that since UNG’s protect telomeres, it helps B cells to continue to proliferate while they mutate their immunoglobulin genes, thus allowing them to mount an effective immune response, according to the study.
The authors noted that their findings may also help non-Hodgkin’s lymphoma cells, which often overexpress AID, to continue to proliferate. Furthermore, by inhibiting UNG, it blocked the growth of human diffuse large B cell lymphoma cells that express AID.
“So UNG can contribute to lymphomagenesis by protecting telomeres from AID-induced damage,” said lead researcher Ramiro Verdun. “We show that cancerous human B cells expressing AID require UNG for proliferation, suggesting that targeting UNG may be a means to delay the growth of AID-positive cancers.”