Acute leukemia is the most common childhood cancer in developed countries and accounts for about one third of all pediatric malignancies. But why do these cancers develop in young children, and, especially, why they are seen primarily in industrialized societies?
A new review paper by noted leukemia researcher Mel Greaves, PhD, FMedSci, FRS, director of the Centre for Evolution and Cancer at the Institute of Cancer Research (ICR) in London, United Kingdom, presents strong evidence that the disease is caused through a "two-step process" of genetic mutation and exposure to infection.
It also suggests that in the second stage of the process, a lack of microbial exposure in early life could increase the risk of developing leukemia. "Paradoxically, we think the problem is not infection but a lack of infection early in life," he added.
Paradoxically, we think the problem is not infection but a lack of infection early in life. Dr Mel Greaves
The review looked at the origins of acute lymphoblastic leukemia (ALL), and specifically B-cell precursor (BCP) ALL, which has been increasing in Europe by around 1% each year. This is part of a 13% global increase in the incidence of childhood cancers, including acute leukemias, as previously reported by Medscape Medical News.
"What we are reporting is what I hope is a resolution to a 100-year controversy on what causes childhood leukemia," Greaves said in a video interview released by the ICR. "What we think is the major cause are patterns of infection that are characteristic of developed societies."
The paper was published May 21 in Nature Reviews Cancer.
Two-Step Process
The new analysis draws on evidence gleaned from 30 years of research, both from Greaves and other experts across the globe, on the genetics, cell biology, immunology, and epidemiology of childhood leukemia. Based on this evidence, the authors conclude that the cause of BCP ALL is multifactorial, involving both patterns of infection and inherited genetics, as well as other modulators of risk.
It is a "paradox of progress in developed societies" in which there is a mismatch between the evolutionary programming of the immune system and modern lifestyles that limit opportunities for microbial exposure early in life.
"The development of leukemia develops in two discrete steps," Greaves explained in the video.
The first step involves a genetic mutation that occurs before birth and predisposes the infant to subsequently developing leukemia. The in utero initiation by fusion gene formation or hyperdiploidy generates a covert, preleukemic clone, but only 1% of children who are born with this genetic change will eventually develop the disease.NThe second step is triggered by infection, which plays a dual role. A lack of microbial exposure early in life results in immune system malfunction, and similar associations have been observed for Hodgkin's lymphoma in young adults and for childhood allergies and autoimmune disease.
Bur while early microbial exposures are protective, later infections trigger the critical secondary mutations if the initial "priming" failed to occur.
"The immune system has evolved to fight infections, and natural infections in the first few weeks and months of life prime the immune system," said Greaves. "In the absence of that priming early in life, by natural infections, later immune response are abnormally regulated."
The risk of developing ALL is also further modified by inherited genetics, chance, and probably diet.
"All of this raises the question as to what parents can do if they are worried about the risk of leukemia," he said.
The risk is relatively low, about 1 in 2000, Greaves explained, and he discussed ways in which that risk can probably be reduced.
Encouraging children to mix with other children and particularly older children would be good. Dr Mel Greaves
"One is not to be overzealous about hygiene and overworried about it," he said. "Encouraging children to mix with other children and particularly older children would be good, and protracted breastfeeding. for 3 to 6 months would be beneficial."
In his paper, he also points out that in addition to lifestyle changes, a more realistic strategy might be to develop prophylactic vaccines that mimic the protective impact of natural infections in infancy. In addition, reconstitution or manipulation of the natural microbiome are approaches being investigated for early-life immune disorders. Another approach is the oral administration of benign synbiotics (bacteria species such as Lactobacillus and oligosaccharides), which can have profound and beneficial modulating effects on the developing immune system.
Greaves also emphasizes that this two-step model applies only to BCP ALL, while the rarer pro-B ALL in infants, childhood acute myeloid leukemia, and childhood lymphoma appear to have different etiology and pathogenesis. Additionally, the data for thymic or T-cell precursor ALL are insufficient to indicate whether this model is applicable.
ALL is probably a preventable disease. Dr Mel Greaves
"What all this research points to me very powerfully is that ALL is probably a preventable disease," he said. "So the challenge is how can you possibly do that? We think the way to do this is to give to infants in the first year of life some form of exposure to microbials that's benign and safe, and I'm reasonably optimistic that in perhaps a 5- to 10-year time frame we'll see this translated into some real benefit."
Pieces Come Together
Commenting on the paper, Gwen Nichols, MD, chief medical officer at the Leukemia & Lymphoma Society, noted that this paper provides good evidence as to why genetic mutations may affect one child and not another.
"However, it's really important to understand that the evidence comes from one subtype of the disease, so we have no idea if this is a mechanism for other types," she told Medscape Medical News.
The paper does suggest that preventing ALL is a possibility. "We might be able to figure out how to avoid that second hit, so to speak, by learning what parts of the immune system are important to stimulate early to avoid cancer," Nichols explained, "And importantly, this may have implications well beyond childhood leukemia." A lack of microbial exposure in early life has also been linked to the development of allergies and autoimmune disease, as noted by Geaves in his interview.
This may have implications well beyond childhood leukemia. Dr Gwen Nichols
"This paper provides good evidence that an interaction between genetics and the immune system play into the development of this disease," she said. "A lot of the pieces of the puzzle are starting to be understood about the interaction of the environment, genetics, and the immune system."
However, Nichols added that while "we are getting much better at figuring out the risks of cancer, we're still a long way off from good prevention."
The research in Greave's lab at ICR was largely funded by the charities Bloodwise and The Kay Kendall Leukemia Fund. Greaves has disclosed no relevant financial relationships.
Nature Rev Cancer. Published May 21, 2018. Abstract
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