New research links the extra chromosome 21 in Down syndrome to altered DNA packaging and excess mitochondria in blood stem cells; the findings offer an explanation for the increased leukemia risk seen in Down syndrome.
by Karen O’Hanlon Corht, PhD
/chromosomes--human-karyotype--down-s-syndrome--trisomy-21-123535483-5ab6b45b6bf0690038b8a259.jpg)
A recent study carried out at Stanford University, the University of Cambridge, the Broad Institute of MIT and Harvard, and the University of Copenhagen sheds light on why children with Down syndrome are at increased risk of developing leukemia. By analyzing more than 1 million individual cells from human fetal liver and bone marrow samples with or without Down syndrome (DS), the researchers built the first comprehensive single-cell multi-omics map of blood development in DS.
[Editor’s Note: Human fetal bone and liver samples were obtained from 15 fetuses with Ts21 12–20 post-conception weeks (PCW) of age and 5 disomic fetuses 11–19 PCW of age, following termination of pregnancy and informed written consent. The human fetal material was provided by the Joint MRC/Wellcome Trust (grant MR/R006237/1) Human Developmental Biology Resource (http://www.hdbr.org), with maternal informed consent, in accordance with ethical approval by the National Health Service (NHS) Research Health Authority, REC Ref: 18/LO/0822. HDBR is regulated by the UK Human Tissue Authority (HTA; www.hta.gov.uk) and operates in accordance with the relevant HTA Codes of Practice.]
Among their key findings was that blood stem cells of fetuses with DS have excess mitochondria, which can lead to leukemia-inducing mutations, and the extra chromosome 21 alters how DNA is packaged inside cells, leading to the dysregulated blood cell production seen in newborns with DS.
The September 25, 2024 open-access Nature article is titled “Single-Cell Multi-Omics Map of Human Fetal Blood in Down Syndrome.” An accompanying News & View article and podcast are also available.
Down Syndrome’s Blood Enigma: Known Leukemia Risk, Elusive RBC Defects
Down syndrome (DS, also known as trisomy 21 or Ts21) is associated with an approximately 150-fold increased risk of developing myeloid leukemia in the first five years of life. The generally accepted model for leukemia development in DS is that somatic mutations in the GATA1 transcription factor in fetal liver hematopoietic stem cells (HSCs) leads to a pre-leukemic state. This spontaneously resolves in most newborns; however, post-birth accumulation of additional mutations in GATA-1 mutant cells can result in leukemia.
Besides the above, newborns with DS often exhibit red blood cell (RBC) defects independently of leukemia-inducing mutations. These defects – which include elevated RBC counts and unusually large RBCs – vary in severity and frequency. Previous studies suggest a multi-factorial etiology with contributions from the local niche, epigenetics, and gene-environment interactions.
Fetal Environments and Genetic Fate: Mapping Blood Cell Development in Down Syndrome
Hematopoietic stem and progenitor cells from fetuses with Ts21 exhibit a unique mutational signature related to oxidative stress, which is a driver of mutagenesis and may cause the GATA-1 mutations mentioned earlier.
The current study, led by Professor Ana Cvejic at the University of Copenhagen, sought to determine if and how Ts21-induced chromatin reshaping contributes to the aberrant blood cell phenotypes seen in DS and how altered chromatin packaging and oxidative stress could lead to the mutations that cause pre-leukemia and leukemia development.
To this end, the researchers explored how fetal HSCs with Ts21 interact with certain microenvironments – in this case fetal liver versus bone marrow, which are the main locations for fetal blood cell development – and how these interactions compare to those in healthy fetuses. Various methods were used, including single-cell RNA sequencing and single-cell in vitro differentiation assays. Spatial transcriptomics and 10X multiome analysis were used to reveal molecular changes in hematopoiesis as cells migrate from the fetal liver to bone marrow and to elucidate how Ts21 impacts this process.
Excess Mitochondria and Reactive Oxygen Species in Down Syndrome
The team studied more than one million individual hematopoietic cells isolated from fetuses with or without Ts21 (control), and examined gene expression, epigenetic control of gene expression, spatial organization of those cells in the liver and bone marrow during blood cell development, and the regional distribution of somatic mutations.
They found that differences in gene expression between DS and control cells, which affected more than one-third of the genes on chromosome 21, were dependent on cell type as well as tissue environment. For instance, they identified a population of HSCs isolated from Ts21 liver that showed increased cell cycle activity, higher oxidative stress, and mitochondrial dysfunction. Notably, GATA1, which controls the development of RBCs, and which is frequently mutated in DS, was among the upregulated genes in HSCs from Ts21 livers.
In line with those findings, the researchers also validated increased mitochondrial mass and elevated reactive oxygen species as phenotypes of Ts21 liver, but not bone marrow HSCs.
Trisomy 21 Impacts Chromatin Packaging and Leads to Red Blood Cell Lineage Bias
Epigenomic and transcriptomic profiling revealed an erythroid bias in Ts21 HSCs, whereby their chromatin and mRNA expression profiles suggested a mature cell state, with broader dysregulation that extended beyond chromosome 21.
The researchers also found that fetal livers with Ts21 were enriched in HSCs and multipotent progenitors – which are the source of all blood cell types throughout life – and that those cells were more proliferative in fetal liver than in bone marrow, indicating that the phenotype is driven by a combination of genetics (i.e., Ts21) and the tissue environment.
In agreement with the RBC defects seen in DS, the researchers found that Ts21 increased the accessibility and expression of regulatory elements and genes critical for RBC differentiation, implying genome-wide chromatin remodeling that destines Ts21 HSCs for the RBC lineage, a finding which was backed up with in vitro cell differentiation assays.
What Does This Mean for Down Syndrome and Leukemia?
The study indicates that altered chromatin organization, gene expression, and oxidative stress in the blood stem cells of individuals with DS may create an environment that is conducive for the mutations that cause leukemia, but follow-up studies are needed: “We discovered that mutations linked to Down syndrome are concentrated within regulatory regionsof genes expressed by HSCs, indicating a plausible mechanistic link between chromatin alterations, oxidative stress, and heightened leukemic risk in Ts21. A future goal is to further refine these observations by pairing cell-type-specific and highly sensitive whole-genome sequencing with multi-omics data across cellular and tissue contexts in the same samples.”
Perhaps most importantly, the study highlights that to truly understand the risk of blood abnormalities in individuals with Down syndrome, we need to look at their genes and the surroundings of their blood cells. It’s not just about the extra chromosome, but also about how that chromosome interacts with the environment inside the body.
[Nature article] [Nature News and Views] [Nature Podcast]
About the Writer
Karen O’Hanlon Cohrt is an independent science writer and editor based in Ireland. After obtaining her PhD in Biotechnology from Maynooth University (2011), Karen relocated to Denmark. There, she held postdoctoral positions in mycology and later in human cell cycle regulation, before moving to the world of drug discovery. Before hanging up her pipette for the last time, Karen worked with yeast, filamentous fungi, bacteria, plants, moth larvae, and mammalian cells, and tried her hand at (almost) everything from Sanger sequencing to genetically modifying disease-causing fungi! Karen is the Editor-in-Chief at CRISPR Medicine News and writes for a number of other outlets on a freelance basis. Her main scientific interests include genetic medicines, rare diseases, and diagnostics. She has been a full-time science writer since 2017, and you can find her other work on her portfolio.