Research led by the University of Copenhagen sheds light on why people with Down syndrome are at higher risk for the blood cancer leukemia.
The study, published in Nature, shows that babies with Down’s have disruptions in gene expression that results in abnormal blood cell differentiation that can lead to blood cancers such as leukemia.
They also have abnormally high levels of mitochondria, which can lead to too many reactive oxygen species in the blood that, in turn, trigger mutations.
“Our study revealed that the additional chromosome 21 alters how DNA is packed inside the cells. This difference affects how certain genes are regulated and can contribute to the development of leukemia,” explained Rebecca Moller, one of the researchers from University of Copenhagen behind the new study, in a press statement.
Children born with Down syndrome are known to have higher numbers of red blood cells than other children. They also face a 150-fold higher risk of developing leukemia in the first five years of life compared with the general population.
To investigate the impact of having a different chromosomal makeup on blood development, the research team used transcriptomics techniques to create a single-cell multi-omics map of the blood using samples from 15 fetuses with trisomy 21 and three fetuses with disomy (a different type of chromosomal abnormality) for comparison purposes.
The investigators found hematopoietic stem cells in the Down’s samples were ready to differentiate. They mapped non-coding elements linked to gene expression in the samples and discovered that the presence of trisomy changed regulatory interactions and disrupted enhancer activity and gene expression needed for healthy red blood cell differentiation.
They also found increased mitochondria and oxidative stress in cells from fetuses with trisomy 21. “These harmful molecules, called reactive oxygen species, are known to attack DNA creating mutations that can lead to pre-leukemia and, eventually, leukemia,” explained first author Andrew Marderstein from Stanford University.
“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 leukemia develop. Understanding these mechanisms is essential for guiding future research in stem cell biology and cancer,” added lead author Ana Cvejic, a professor at the University of Copenhagen.
