According to a new study by researchers at the Linda Crnic Institute for Down Syndrome, the reason that children with Down syndrome have a drastically elevated risk of leukaemia is due to a more prevalent condition increasing blood stem cell mutation.
Children with Down syndrome are 20-times more likely to develop acute lymphocytic leukaemia (ALL) and 150-times more likely to develop acute myeloid leukaemia (AML) compared to their typical peers. The researchers found that the reason for this is that they are more likely to present with clonal haematopoiesis (CH), a process in which a blood stem cell acquires a genetic mutation that promotes replication.
The findings add to a growing body of evidence linking immune dysregulation to a very different disease spectrum, whereby people with Down syndrome are highly predisposed to certain diseases such as leukaemia and autoimmune disorders, while being highly protected from others, such as solid tumours.
“We found a higher-than expected rate of CH in individuals with Down syndrome between the age of one to 20 years old,” said study author Dr Alexander Liggett, who as a doctoral candidate led the study in the lab of Dr James DeGregori, Professor of Biochemistry and Molecular Genetics. “It is a surprising finding, as the phenomenon is typically only observed in elderly people.”
The researchers used an advanced sequencing technique that they had developed, called FERMI, to blood samples from the Crnic Institute Human Trisome Project Biobank. Mutations were more likely to be detected in Down’s syndrome and also more likely to be oncogenic. In elderly people, oncogenic mutations are commonly found in the genes DNMT3A, TET2, ASXL1, TP53, and JAK2. In people with Down’s syndrome, oncogenic CH was found to be dominated by mutations of the TET2 gene.
“Given the increased risk of leukaemia that accompanies clonal expansion of blood cells carrying oncogenic mutations, these expansions may become an important biomarker of cancer risk in the future,” said Dr Liggett.
The study also found that CH in Down syndrome is associated with immune dysregulation biosignatures linked to diseases co-occurring with Down’s syndrome, including thyroiditis, Alzheimer’s disease, and leukaemia. This discovery opens new avenues in understanding the way CH impacts an array of health outcomes in Down syndrome and how to potentially counteract its effects.
“This is truly transformative. This team has identified a new trait of Down syndrome that has strong implications for understanding the appearance of comorbidities more common in this population, such as leukaemia and premature ageing,” said Dr. Joaquin Espinosa, Executive Director of the Crnic Institute. “The next step is to define the long-term impacts of this precocious clonal hematopoiesis and how to prevent its harmful effects.”
Source: News-Medical.Net
Journal information: Liggett, L.A., et al. (2021) Precocious clonal hematopoiesis in Down syndrome is accompanied by immune dysregulation. Gut. doi.org/10.1182/bloodadvances.2020003858.
