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A team of scientists has uncovered new evidence that some cases of a subtype of childhood leukaemia may develop before birth, shedding light on how the disease evolves over time.
The study, led by ongoing collaboration between The Institute of Cancer Research (ICR), the Karolinska Instiutet and Uppsala University in Sweden, represents the first systemic analysis of neonatal blood spots taken at birth from children who later developed a rare subtype of paediatric acute lymphoblastic leukaemia (ALL) called iAMP21.
By providing new insights into this specific ALL subtype and revealing that some of these alterations can already be present in newborns, years before diagnosis, the researchers have demonstrated the feasibility of early detection of disease-associated genetic alterations at birth.
The work was funded by The Institute of Cancer Research, London – which is both a research institute and a charity – and the Swedish Childhood Cancer Society. The findings have been published in the journal Haematologica.
Investigating an unanswered question
Paediatric ALL originates in a type of white blood cell called lymphocytes, which can grow uncontrollably in the bone marrow. It is the most common type of leukaemia diagnosed in children under the age of 18, with around 400 cases diagnosed each year in the UK.
Thanks to pioneering work carried out at the ICR by Professor Sir Mel Greaves, who transformed the understanding of leukaemia, scientists have long been aware that certain forms of childhood leukaemia may begin before birth. However, exactly when key genetic changes occur and how the different subtypes of ALL evolve over time have remained unclear.
To help overcome this hurdle, the team focused their study on iAMP21, which accounts for around two per cent of ALL cases. This high risk ALL is typically diagnosed in older children with low white blood cell counts, raising questions about how long it may have been developing before symptoms become apparent. Specifically, the team addressed whether the defining genetic changes in iAMP21 arise prenatally or postnatally.
Tracking cancer back to birth
To establish the timings of these events, the team analysed neonatal bloodspot samples provided by the Center for Medical Mass Screening in Sweden. In the UK and in Sweden, these small blood samples are collected shortly after birth for routine screening tests, commonly referred to as heel prick tests.
Within certain protocols and guidelines, the samples can provide a unique research opportunity for understanding cancer initiation and observing biological changes over time.
By comparing neonatal blood spots with later samples taken at diagnosis from two patients, the researchers were able to trace the clonal evolution of iAMP21. They identified amplification of chromosome 21 – a genetic abnormality and hallmark of iAMP21 – already present at birth. This alteration was found in a small number of blood cells, suggesting they formed part of a pre-ALL population that existed long before the disease become clinically apparent.
Multiple genetic pathways
The team also found evidence that this genetic alteration continues to evolve after birth, with additional mutations accumulating over time. Although some of the earliest changes arise before birth, they are not sufficient to cause disease on their own. Instead, this develops over several years, with children typically going on to be diagnosed with overt ALL at the average age of nine.
In one patient analysis, the team identified a genetic rearrangement within the bloodspot sample identical to the one seen at diagnosis, indicating that a pre-ALL clone was already present at birth. In the other case, early genetic alterations were detected at birth, but they had evolved into more complex changes by the time the disease was diagnosed.
Together, the results show that iAMP21 can arise through multiple pathways – either from very early stages that occur before birth, or from genetic alterations that develop later but build on earlier abnormalities.
Senior author Professor Britt Gustafsson, Professor and Senior Consultant in Pediatric Hematology at Karolinska University Hospital and Uppsala University, said: “While promising, this research raises important possibilities and ethical considerations. If pre-leukaemic changes can be detected at birth, it prompts questions about screening, early detection and whether identifying at-risk individuals would be beneficial or potentially anxiety-inducing for families.”
Effects on future research
Although the study involved only a small number of patients, it provides some of the clearest evidence to date that key genetic events in iAMP21 can originate before birth.
Senior author Dr Tony Ford, who was a Senior Staff Scientist in the Centre for Evolution and Cancer at the time of the research, said: “Although there are no immediate clinical applications for patients, the study progresses our understanding of the biological processes driving iAMP21 development, allowing for future explorations into whether earlier detection or intervention could be possible.”
First authors Dr Gustaf Leijonhufvud and Dr Viktor Ljungström, Affiliated Researchers in the Department of Women's and Children's Health at Uppsala University, said: “Further research will of course be needed to expand this approach to additional genetic subtypes of paediatric ALL that have not yet been studied using neonatal blood spots. We now have the infrastructure and access to larger patient cohorts and stored neonatal blood spots, enabling broader investigations into the prenatal origins of childhood leukaemia.
“A better understanding of whether specific leukaemia subtypes originate prenatally or not could open the door to preventive strategies or very early interventions. The immediate number of beneficiaries is unclear, but this research certainly has potential global relevance for childhood leukaemia.”
The ICR has been instrumental in driving progress in leukaemia. Find out more about how we have led the way in leukaemia research over the decades.
Banner Image: A small, hypolobated megakaryocyte in a bone marrow aspirate, typical of chronic myelogenous leukemia. (Credit: Difu Wu/CC BY-SA 3.0)
