Down's syndrome leukaemia risk linked to blood stem cell differentiation

The extra copy of chromosome 21 in individuals with Down's syndrome disrupts blood cell development during fetal growth, explaining their increased risk of developing leukaemia during childhood.

Down's syndrome is caused by having an extra copy, or trisomy, of chromosome 21. Compared to the general population, children with Down's Syndrome face a 150-fold increased risk of developing myeloid leukaemia, a type of cancer that affects blood stem cells. Newborns with Down's syndrome often exhibit abnormalities in their red blood cells, yet the severity and occurrence of the abnormalities vary. The contribution of additional factors such as epigenetics, the cellular microenvironment, and gene–environment interactions to these abnormalities are unclear.

Professor Ana Cvejic from the University of Copenhagen, Denmark, and senior lead scientist on the study, said: 'This study is the largest of its kind, and it shows that the environment and genetic makeup of cells are crucial in understanding how blood cells and leukaemia develop. Understanding these mechanisms is essential for guiding future research in stem cell biology and cancer.'

In the study published in Nature, researchers isolated blood cells from the liver and bone marrow, the two main sites of blood-cell production during fetal development, from fetuses with and without Down's syndrome. They then used multiple techniques to sequence the DNA in over 1.1 million cells they isolated.

Researchers found that the trisomic blood cells displayed widespread gene dysregulation but differently across the cell types, particularly affecting blood stem cells. These cells exhibited increased expression of genes responsible for red blood cell production, oxidative stress, and dysfunction of the cell's energy-generating structures called mitochondria.

Mitochondrial dysfunction can lead to the production of reactive oxygen species, which damage DNA and can contribute to leukaemia. Notably, the analysis also revealed that no single gene on chromosome 21 drove the genetic changes, but that the changes required the increased expression of at least one-third of the genes on chromosome 21.

Overall, the findings of this study indicate that the disruptions in blood cell development in Down's syndrome are caused by widespread gene dysregulation due to trisomy 21, creating conditions that increase the risk of myeloid leukaemia. Furthermore, the sequencing data generated in the study could serve as a resource for future research on how trisomy 21 influences leukaemia and other cancers in Down's syndrome.