New research has endorsed a long‑standing idea explaining why acute lymphoblastic leukaemia (ALL) – the most common cancer in children – appears abruptly in early life, often in otherwise healthy individuals, with no obvious environmental trigger.
The new study, carried out by researchers at The Institute of Cancer Research, London, has provided some of the clearest experimental evidence yet that when children encounter everyday microbes may be just as important as whether they do.
Using a carefully designed mouse model, the researchers showed that delayed exposure to common, usually harmless infections can trigger leukaemia in genetically susceptible individuals. Crucially, early-life exposure to diverse microbes appears to protect against the disease, opening the door to potential strategies for prevention rather than treatment.
The research was supported by a Cancer Research UK programme grant, along with funding from The Children’s Cancer and Leukaemia Group, the Artemis Wood Fund, and Prevent ALL – a charity set up by the family of ALL survivor Tommy Edwards.
The findings, published in the journal Haematologica, lend strong support to the causal mechanism for childhood ALL first proposed many years ago by Professor Sir Mel Greaves, Group Leader of the Biology of Childhood Leukaemia Group at The Institute of Cancer Research (ICR).
A two‑step origin for childhood ALL
Childhood ALL – particularly the most common subtype, B cell precursor ALL – begins before birth when the baby is in the womb. Professor Greaves and his team have previously found that children who later develop ALL already carry the first genetic ‘hit’ before they are born. These initiating lesions most often take the form of a gene fusion called ETV6::RUNX1 or an abnormal number of chromosomes, known as hyperdiploidy.
On their own, however, these genetic changes are not enough to cause cancer, and most children who are born with them never have a leukaemia diagnosis. A second step is required after birth: an additional genetic change or mutation in developing immune cells, usually involving deletions in genes that control normal B‑cell development. These secondary changes are frequently driven by enzymes known as RAG1 and RAG2, which can inadvertently mutate DNA in the process of helping immune cells generate diverse antibodies.
Epidemiological studies have long suggested a link between early-life microbial infection and this second step. Children who are born by sterile C-section, are primarily formula-fed or have low social contact during the first year of life have a higher risk of ALL. The theory proposes that a lack of early immune ‘training’ leaves the immune system prone to exaggerated or poorly regulated inflammatory responses when it later – for example, at primary school – encounters common infections, increasing the chance of cancer‑promoting genetic mistakes.
Until now, however, this idea had not been directly tested in an experimental model.
Exploiting a serendipitous scenario
To address this, the research team turned to mice genetically engineered to carry the ETV6::RUNX1 fusion – the same initiating lesion found in many children with ALL. On their own, these mice rarely develop leukaemia, closely mirroring the human condition.
What made the experiment possible was an unexpected difference between two mouse facilities run by the ICR before the Covid‑19 pandemic. Both facilities were officially designated SPF (specific pathogen free), meaning that they excluded known disease‑causing pathogens. But, in practice, they differed markedly. One site had an ultra‑clean environment with virtually no endemic microbes, while the other harboured about 10 persistent and other occasional non‑harmful microbes, including bacteria, viruses and unicellular parasites.
The researchers transferred genetically susceptible mice shortly after weaning from the ultra‑clean facility into the microbially richer one. The result was striking. Close to a quarter of these mice went on to develop ALL.
In contrast, mice born and raised entirely in either environment did not develop the disease. Nor did mice transferred into the ‘dirty’ facility after it had been fumigated during the pandemic, which eliminated the endemic microbes. The disease appeared only when genetically susceptible mice encountered common infections late, rather than from birth.
Analysis of the animals’ gut microbiomes helped explain why. Mice in the microbially richer facility had greater bacterial diversity and higher levels of bacteria known to support immune system development.
Together, the findings show that common infections can indeed trigger leukaemia, but only if the immune system has not been properly primed in early life.
Future prevention in children
The study provides powerful experimental backing for the idea that there is a critical window in infancy, from birth to the end of weaning, when exposure to a broad range of microbes helps calibrate the immune system. If this window is missed, later infections may provoke abnormal immune responses that increase cancer risk in those already carrying pre‑malignant cells.
Although no one is recommending deliberate exposure to potentially dangerous infections, the findings add to growing concerns that modern lifestyles with greatly reduced microbial exposures may have unintended consequences as well as benefits. They also raise the possibility that carefully designed interventions – such as microbiome‑supporting diets or probiotics in infancy – could one day reduce the risk of a common childhood cancer.
Senior author Professor Greaves said: “These mouse data provide endorsement of our causation model for childhood ALL and encourage the notion that ALL might be preventable by early-life microbiome enrichment – possibly by oral probiotics. Decades after I first proposed the two-step delayed infection model, these results support the idea that timing – not just genes and not just germs – may be the missing piece in understanding childhood leukaemia.”
Joint first author Elham (Ely) Shamsaei, Higher Scientific Officer in the Division of Cancer Biology at the ICR, said:
“For families affected by ALL, this study does not change current clinical advice or treatments. But it does point towards a future in which preventing the disease might be possible, not through anti-cancer medications, but by restoring a more natural relationship between the developing immune system and the microbial world.”
Image credit: Gerd Altmann from Pixabay (modified)