How do early infections or vaccinations protect some children who are at risk of leukaemia? These scientists think they might know...
When the immune system misfires, molecules that help generate our immune diversity may also cause collateral damage that drives the development of leukaemia in some children.
The blood cells of many newborns – around 1 in a hundred – carry genetic faults that are known to be critical for the development of acute lymphoblastic leukaemia (ALL) – the most common form of childhood cancer. But only one in 10,000 children will actually develop a cancer, so researchers have been hunting for the additional steps that are necessary for leukaemia to form.
Immune diversity: the good and the bad
Researchers in California, together with Leukaemia & Lymphoma Research-funded scientists in London, have homed in on molecules in our cells that tweak the DNA of immune genes. These normally generate the diverse immune responses needed to fight off a multitude of infections. But they suspect friend may turn foe when an immune system malfunctions in response to recurrent and intense infections occuring later in life than usual. When this happens, these enzymes can become over-activated and start snipping the DNA more randomly. If a child already carries a genetic fault in their developing blood cells, additional errors in key gatekeepers against uncontrolled cell growth can mean a cancer can start to form.
If true, it would be an unlucky collision of a founding genetic fault, an immune over-reaction to a late infection and additional key control genes being hit.
The researchers were building on evidence that suggests vaccination against certain pathogens, such as Haemophilus influenzae type B (HIB), during early childhood reduces the risk of leukaemia. Other evidence also shows that attendance at nursery as infants, which exposes children early in life to common infections, also provides some protection against childhood ALL.
A team of scientists led by Prof Markus Müschen at University of California San Francisco and Prof Mel Greaves at The Institute of Cancer Research reported their findings in leading journal Nature Immunology.
Previous studies had flagged up AID and RAG as possible culprits for some of the genetic faults seen in ALL. These are enzymes that, when faced foreign invaders like bacteria and viruses, are activated in certain “B” white blood cells to reprogram DNA to generate a diversity of immune antibodies to counter the challenge. To add weight to this, the team noticed that genes frequently deleted in patients bore the hallmarks of changes induced by RAG and were also targets of AID. What’s more, childhood ALL patients with higher than average AID levels had a poorer outlook in clinical trials.
The team analysed “pre-leukaemia” cells in mice that carried a key genetic fault, known as ETV6-RUNX1. They mimicked repeated infection to trigger an immune response and studied what happened when these cells lacked one of AID or RAG, and also when both enzymes were present. When both enzymes were active, the mice quickly developed leukaemia. With either one was absent, on the other hand, leukaemia did not develop or it developed after a prolonged period of time.
To understand this better, the team also engineered normal human immune cells so they could turn on and off AID and RAG activity alone or in combination. When they switched on either AID or RAG alone, there was some small-scale genetic damage. When they activated both AID and RAG, the amount of genetic damage shot up just like it does when pre-leukaemic cells transform to leukaemic cells.
These findings suggest that over-active AID and RAG, working together, could be critical in laying down the extra faults needed for full-blown leukaemia to start from abnormal "pre-leukaemia" cells. It's far from proven that this is major contributor in real-life situations, but it's an intriguing piece in the puzzle.
Prof Müschen said: “These experiments provides a potential explanation for the striking epidemiological finding that systematic introduction of vaccination programs during infancy dramatically reduced the risk of childhood leukemia.”
The team also found that B-cells were prone to premature activation of AID, leading to a greater vulnerability to genetic damage. When they studied a signalling molecule – a ‘cytokine’ called IL-7 – however, they found that in both mouse and human cells, its activity seemed to safeguard against this premature activation. As IL-7 is important in maintaining a healthy balance of other immune cells, it suggests a mechanism that links the immune environment to proper immune cell maturation.
"Two hits" are needed
Together, these findings support Prof Greaves’ “delayed infection hypothesis” for the beginnings of childhood ALL, built on an idea of a “two-hit” process. First, some children acquire a genetic fault – the first “hit” – in the womb, which creates a group of abnormal immature white blood cells that are essentially ‘silent’. Next, after birth, other genetic errors – the second “hits” – in key gatekeeper genes tip these cells out of control, causing full-blown leukaemia to develop. In many cases, these second hits are down to a misfiring immune response caused by excessively strong and long-lasting inflammation, potentially as the result of delayed exposure of an under-developed immune system to an infection. Although not conclusive, the study points to the molecular players in our cells that may drive this.
Prof Greaves, whose work we have supported for decades, summed up: “The study provides mechanistic support for the hypothesis that infection or inflammation promotes the evolution of the common form of childhood leukaemia and that the timing of common infections in early life is critical.”
So it is the timing of the infection that really is key – mild infections early in infancy, like the ones encountered in nursery or as a vaccine, can help prime an appropriate immune system, but more serious infections that cause an intense immune response later in childhood may lead to some collateral damage.
The researchers focused on HIB, a bacterial infection, and so more work is needed to test whether the same mechanisms are at work for other types of infections, like viruses. The work also focused on one initiating gene fault – ETV6-RUNX1 – so further work should look at others to see whether the same processes are at play. And we should bear in mind this is an experimental set-up, so the findings should be treated with a note of caution – more work is needed to test the impact of actual vaccines or real previous illnesses.
It is important to stress also that these findings are relevant to the children who are born with ‘silent’ “pre-leukaemia” cells, the vast majority of whom will not develop leukaemia at all. But if we can identify these newborns, and we can take steps to reduce the chances of a problematic immune response – either through vaccination or mild early exposure – then we may be able to stop many of these cancers in the first place.
Swaminathan S, Klemm L, et al. Nature Immunology, advance online publication. doi:10.1038/ni.3160
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This article is licensed under a Creative Commons Attribution 4.0 International License .
This post was edited 19/05/15 to emphasise that the effects relate to infections in specific contexts and that these conclusions are drawn from an experimental system.