Tracking the viral link to lymphoma

Epstein-Barr has genes that can either suppress or promote blood cancer

While scientists have known for years that the Epstein-Barr virus harbors genes that can cause lymphoma, researchers now report evidence that the virus also carries the opposite cargo — a cancer suppressor gene. This seems to work by alerting the immune system to renegade cell growth caused by the virus, directing the body to attack, researchers report March 12 in the Journal of Clinical Investigation.

The viral gene, called EBNA3B, might thus help maintain chronic Epstein-Barr infection of cells without allowing unchecked cell growth — a trade-off that represents an evolutionary adaptation to minimize cancer risk to the host, virologist Martin Allday of Imperial College London and his colleagues conclude.

But the virus’s cancer-promoting genes occasionally win out, leading to malignancies including Hodgkin, Burkitt and other B-cell lymphomas. The researchers demonstrate that this happens — at least some of the time — due to a mutation of EBNA3B. In tests of 39 samples of lymphomas containing Epstein-Barr virus, researchers found at least nine had mutated viral EBNA3B.

To assess the mutation’s impact, the researchers used mice engineered to carry human immune system components. The team exposed some of the mice to virus lacking the EBNA3B gene, approximating the effect of a gene hobbled by the mutation. The other mice were exposed to virus that carried the protective gene. Mice infected with Epstein-Barr without the gene developed tumors in four weeks, whereas those given the virus with the EBNA3B gene intact didn’t, indicating the gene encodes a protein that somehow suppresses tumor formation.

Further testing showed that immune system B cells infected with Epstein-Barr harboring normal EBNA3B secreted an attractant compound called CXCL10, which made the cells more identifiable to the human immune T cells carried by the mice. In these mice, T cells were more likely to kill the infected cells, inhibiting proliferation and, hence, cancer than were T cells in the other mice.

Epstein-Barr virus is extremely common in the population and is best known as the cause of infectious mononucleosis. It is considered a latent virus because it can hide out in B cells for decades, even after arriving in an infection that went unnoticed.

The link between a reawakening of Epstein-Barr in the body and lymphoma has been murky, but trends have turned up in past studies.

People with suppressed immunity face a heightened risk of developing a B-cell lymphoma linked to Epstein-Barr. That group would include the elderly, people with HIV and those who have received an organ or a stem cell transplant and who are taking immune-suppressing drugs. “This gene could play a role there,” says Stephen Gottschalk, a pediatric oncologist at the Baylor College of Medicine and Texas Children’s Hospital in Houston. “Therefore, it’s quite fascinating.”

A test for viral EBNA3B status in immune-suppressed people might have benefit, he says, particularly in transplant recipients who are largely past the risk of organ rejection but still taking immune-dampening drugs. The value might be in the timing. “If we diagnose lymphoma as early as possible, the outcome is better,” he says.

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