Warren Cornwall in Science:
For years, scientists have noticed an interesting pattern of cancer among children. Those who went to day care early in life were less likely to later develop the most common childhood cancer: acute lymphoblastic leukemia (ALL). Now, a 7-year study appears to have unraveled the molecular mechanism driving ALL. The work may explain why early exposure to infections in places such as day cares seems to protect against the disease and why unrelated vaccines help guard against this cancer. For Mel Greaves, a cancer cell biologist at the University of London’s Institute of Cancer Research, the finding provides an explanation for the hypothesis he has long promoted: that when infants in modern societies are sheltered from routine infections, their immune systems are more likely to overreact during later infections, paving the way for ALL. “I see it as the missing link,” he says of the new research.
Most childhood ALL involves a malfunction of B cells, the scouts of the immune system that patrol the bloodstream looking for intruders like viruses and bacteria; they make antibodies that help fight infections. But with leukemia, the immune system goes haywire, churning out flawed, immature B cells at a prodigious rate and crowding out healthy blood cells. Normal B cells are a marvel of adaptability. As they mature, they reprogram their own DNA, enabling the immune system to produce millions of different B cells programmed to recognize the vast range of potential infections. The DNA rearrangement relies on a sequence of enzymes. First, proteins known as RAGs cut and paste whole chunks of DNA. After that, another enzyme, AID, goes to work “fine-tuning” the DNA by altering single nucleotides. But Greaves and colleagues suspected this process could go awry, introducing mutations that create flawed B cells that could cause leukemia. In a series of experiments, they found evidence that much of the problem lay with a breakdown in the orderly sequence of gene editing during infections. Rather than the RAGs doing their business and then stepping aside for the AID, the AID kicked in simultaneously, potentially increasing the risk of gene-editing errors. These tantalizing results came to a head in an experiment on mice with a genetic abnormality linked to childhood ALL. The condition, in which two genes associated with blood formation are fused together, is found in the cord blood of 1% of all newborns. But most children with it never go on to develop full-blown ALL. The researchers wondered if unregulated mutations set off by repeated infections later in childhood could make the difference, triggering the leukemia.