Taylor B. Poston
Childhood acute leukemia is the most common pediatric cancer in the developed world. It accounts for one-third of all cases and affects 1 in 2000 children under the age of 15. More specifically, acute lymphoblastic leukemia (ALL) is the most common pediatric leukemia and case numbers have been increasing steadily at 1% each year. Prior to recent advances in chemotherapy, ALL was lethal; today, it has a 90% cure rate. This is a substantial advancement; however, the treatment is toxic, traumatic, and causes long-term health problems. To better treat or prevent ALL, the cause must first be determined.
Mel Greaves, a leading cancer biologist at the Institute of Cancer Research in London, compiled evidence from decades of research on ALL, specifically the subtype that affects developing B cells, and outlined his findings in a Nature Reviews Cancer article published in May 2018. From this research, he proposes that ALL develops in two distinct steps – or a “two-hit” hypothesis. First, a genetic mutation is acquired in approximately one in 20 children that are developing inside their mother’s uterus. This mutation is a result of two genes (ETV6 and RUNX1) combining to create a hybrid ‘fusion gene’. Then, after birth, there are abnormal secondary genetic changes in the pre-leukemic cells that lead to overt ALL development.
Stopping the first mutation is unlikely because this occurs during fetal development. Thus, it is not inherited from either parent. However, a better understanding of how the abnormal second event occurs in children could provide answers for more effective treatment or prevention. Greaves suggests that microbial exposure early in life, even though it may result in sickness, is protective, but in its absence, later infections, like the common cold or flu, trigger an abnormal immune response leading to chronic inflammation that causes critical secondary mutations necessary for ALL development.
Exposure to benign bacteria or viruses in the first year of life could be sufficient to properly prime, or set up, the child’s immune system and prevent the cancer-forming secondary mutations. Greaves cites studies demonstrating that factors like going to daycare as a baby (microbial exposure), having older siblings (that likely bring microbes home), breastfeeding, and being born via vaginal delivery are correlated with reduced risk of ALL development. Vaginal delivery exposes newborns to benign microbiota (healthy bacteria that live in our bodies), which is prevented in the case of cesarean delivery. Breastfeeding provides antibodies, microbes (Lactobacilli), and also nutrients that support the infant’s intestinal microbiome (Bifidobacteria). A reduced ALL risk of approximately 20% is associated with breastfeeding 6 months or more. These data are also supported by animal models. Mice that have been modified to express the hybrid gene develop cancer after being transferred from sterile conditions to a non-germ-free environment.
Childhood ALL can be viewed as a consequence of modern society’s progress. Behavioral changes, like hygiene and cleanliness, have reduced interactions with microbes early in life. People in developed countries have fewer bacterial species in their gut microbiome, which help digest food and control inflammation, due to this reduced exposure. This creates an evolutionary mismatch for our immune system because microbial exposure has imprinted important adaptations. Childhood ALL may not be the only consequence, because similar associations have been found for Hodgkin lymphoma, allergies, and autoimmune diseases like type-1 diabetes. The theme for these clinical outcomes is that common infections early in life have an impact on later immune responses and disease development. Preventing exposure to pathological microorganisms has been beneficial due to major reductions in infant mortality, but it may also have unintended consequences like an underdeveloped microbiome and the subsequent development of chronic disease.
This hypothesis will benefit from further investigation, particularly animal modeling, but carries significant health consequences, including the potential that most cases of childhood ALL are preventable. Advocating for behavioral changes like daycare attendance and protracted breastfeeding could help, but would be difficult to achieve. Greaves suggests a vaccine that mimics the protective impact of acquiring benign bacteria in early life might be more realistic. Reconstitution or manipulation of the natural microbiome is a strategy currently being investigated for autoimmune and allergic conditions and could be applied to ALL. Previous data demonstrate that oral administration of benign bacteria that make up our gut microbiome can have beneficial effects on the developing immune system. Greaves and his research team are investigating which microbes are the most important for priming the immune system. This research has begun in mice, with the aim to begin human trials in a few years. Theoretically, a yogurt blend of less than ten microbial species, given to young children, could be enough to reduce cases of ALL and other chronic illnesses.
Greaves, M. (2018). A causal mechanism for childhood acute lymphoblastic leukaemia. Nat Rev Cancer, 18(8), 471-484. doi: 10.1038/s41568-018-0015-6
Papaemmanuil, E., Rapado, I., Li, Y., Potter, N. E., Wedge, D. C., Tubio, J., . . . Campbell, P. J. (2014). RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia. Nat Genet, 46(2), 116-125.