Reacción a "Alterations in DNA packaging could explain a higher risk of leukemia in children with Down syndrome"

This is a great article in the sense that it gives explanations as to why the evidence for blood diseases in these patients was so far unknown. To begin with, they have used a single cell approach (much more accurate than a bulk approach or sorting) and have sequenced a large number (1,000,000) of cells (50 times more than to date) which has allowed them to map the haematopoiesis of patients with Down's syndrome versus the non-Down's syndrome population.

Using haematopoietic stem cells from foetal liver (foetal haematopoiesis) and foetal bone marrow, they demonstrate, by means of gene expression and chromatin accessibility at the single cell level, how there is a subpopulation of haemopoietic stem cells (HSC) from Down's syndrome patients that are biased towards the erythroid lineage and very little or none towards the granulocytic lineage, which is what is observed in the non-Down's syndrome population. All this induces the expression of the transcription factor GATA1, which is essential for erythroid development and hence why Down's syndrome patients have polycythaemia, and not due to a GATA1 mutation, as the disease is studied in Down's syndrome cell models.

This dysregulation of HSC gene expression, coupled with the fact that i) the authors have also demonstrated defects in mitochondria leading to increased ROS (oxidative stress) in HSCs from Down syndrome patients, and ii) the mutations seen in cells from these patients are concentrated in regions regulating the expression of genes expressed by HSCs, would explain why Down syndrome patients are more prone to leukaemia.