Modelling the Role of the Microbiome in Infection Triggered Acute Lymphoblastic Leukaemia
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Embargo End Date
2027-05-13
ICR Authors
Authors
Shamsaei, E
Document Type
Thesis or Dissertation
Date
2026-05-13
Date Accepted
Abstract
B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common childhood malignancy in
developed countries, with genetic diversity dominated by ETV6::RUNX1 fusion and hyperdiploidy
subtypes. BCP-ALL is initiated in utero but requires additional postnatal genetic events for overt disease
development. Our 'delayed infection' hypothesis proposes that insufficient microbial exposure early in life
leads to abnormal immune responses, increasing the risk of leukaemia, while early microbial exposure
provides protection.
We investigated this hypothesis using an ETV6::RUNX1 transgenic mouse model. Transgenic mice
transferred from a specific pathogen-free (SPF1, 'clean') facility to an endemic microbe-rich (SPF2, 'dirty')
environment at 5–8 weeks of age developed BCP-ALL with approximately 25% penetrance. Interestingly,
mice born and raised in the 'dirty' environment before fumigation did not develop leukaemia. Moreover,
those moved to sanitised SPF2 conditions post-fumigation also did not develop leukaemia. Microbiome
analyses revealed distinct gut microbial compositions between housing facilities and between pre- and
post-fumigation periods; mice from pre-fumigation 'dirty' housing exhibited higher microbial diversity,
including abundant anti-inflammatory, short-chain fatty acid-producing genera.
Our research also explored gut microbiome stability by studying the impact of ageing, antibiotics, and
microbial transplantation methods. Faecal microbiota transplantation (FMT) experiments confirmed that
the gut microbiome could be significantly altered.
This work demonstrates that exposure to common endemic and occasional sporadic microbes can
promote BCP-ALL initiated by the ETV6::RUNX1 gene fusion, highlighting murine norovirus as a potential
trigger for ALL in this model. Our findings support the 'delayed infection' hypothesis, indicating early-life
microbial exposure may protect against infection driven leukaemia, emphasising the potential role of the
gut microbiome in leukaemia risk and prevention strategies.
Finally, preliminary human microbiome analysis revealed that healthy control children showed
significantly higher gut microbial diversity than children with ALL, independent of age and sex. Beta
diversity analysis also indicated distinct microbial community structures between healthy controls and
ALL groups, supporting a potential protective role of a diverse microbiome in early life.
Citation
2026
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Biol Childhood Leukaemia