Why children with Down’s syndrome are predisposed to developing leukaemia

The study links genetic and regulatory changes to increased erythrocyte production and leukemia risk while also identifying oxidative stress as a key factor in these abnormalities.

In a recent study published in Nature, researchers examined the cellular features and molecular mechanisms that increase the vulnerability of children with Down syndrome to leukemia or blood cancer.

Background

Down syndrome, a genetic disorder characterized by an extra copy of the 21st chromosome (trisomy 21), affects around one in every 1,000 individuals and raises the chance of developing pediatric leukemia within the initial five years.

During blood cell development, stem cells transform into myeloid or lymphoid lineages. Myeloid leukemia involves an excess of myeloid-lineage progenitor cells, namely those that give birth to red blood cells (RBCs), platelet-forming megakaryocytes, and innate immune cells like monocytes and macrophages.

A 2021 study found that trisomy on chromosome 21 is necessary for leukemia to start in fetal liver cells but not for myeloid leukemia progression. Previous research on Down syndrome showed increased erythroid-megakaryocyte progenitor cells in fetal livers but not within the bone marrow.

About the study

The present study researchers combined single-cell ribonucleic acid sequencing (scRNA-seq) and chromatin accessibility with spatial transcriptomics to explore epigenetic and transcriptomic changes that increase susceptibility to leukemia among Down syndrome children.

RNA transcription studies assessed gene expression. Deoxyribonucleic acid (DNA) accessibility to the transcriptional machinery indicated the epigenetic regulation of gene expression. Single nucleus ribonucleic acid sequencing (snRNA-seq) and a single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) assessed chromatin changes and gene expression.

Researchers evaluated the spatial distribution of cells within the liver and bone marrow, primary sites of producing blood cells in the fetus. Flow cytometry compared the cellular compositions of trisomic and disomic fetal livers. Characterizing the epigenome of single hematopoietic cells in trisomy fetal liver revealed gene-regulatory systems that control phenotypes.

Researchers examined genetic variations linked with blood illnesses to identify genes accessible to the transcriptional machinery and whose activation may contribute to the erythroid bias in trisomic hematopoietic stem cells (HSCs) from the fetal liver. They used the Eukaryotic Promoter Database (EPD) and the activity-by-contact (ABC) model to examine transcription factor enrichment in promoters and enhancers, respectively.

Results

Trisomic fetal livers had an increased percentage of erythroid cells and platelet progenitors (megakaryocytes) and abnormal B cell development. They showed enrichment of cells that can convert to any mature blood cells throughout life, namely HSCs and multipotent progenitors (MPPs), which are more proliferative than those seen in disomic fetal livers. Notably, this increased proliferative ability was absent in trisomic bone tissues. Trisomic bone marrow demonstrated abnormal formation of bone progenitor cells, which might explain the postnatal bone deficiencies seen in Down syndrome.

Children with Down's syndrome are more likely to get leukaemia: stem-cells hint at whyPlay

The GATA-binding factor 1 (GATA1) gene showed upregulation in HSCs from trisomic fetal liver. The increase is significant since GATA1 encodes transcription factor proteins that regulate the formation of megakaryocytes and erythroid cells and undergo mutations in children with Down syndrome developing myeloid leukemia. GATA1 mutations, in conjunction with trisomy 21, increase the number of megakaryocytic progenitor cells, impede the terminal maturation of megakaryocytes, and cause leukemia.

Trisomy 21 alters chromatin (DNA in packed form). Ts21 HSCs are primed for the erythroid lineage by chromatin modification. The reshaping allows transcription factors such as Runt-related transcription factor 1 (RUNX1), MDS1 and EVI1 complex locus (MECOM), and GATA1 to bind with DNA, particularly at regulatory areas known as enhancers, which promote transcription.

Furthermore, GATA1 is altered among trisomic HSCs, making it more accessible to transcription factors compared to disomic HSCs. The finding may explain, at least partially, the overexpression of GATA1, which may enhance the megakaryocytic and erythroid bias of trisomy 21 HSCs.

Conclusion 

The study showed that trisomy 21 triggers a series of events that predispose individuals with Down syndrome to develop myeloid leukemia. The events include the enrichment of proliferative, erythroid-biased fetal HSCs with increased ROS-related oxidative stress and mitochondrial dysfunction, which facilitate the development of GATA1 gene mutations. The study suggests a selective procedure, choosing the most adapted trisomy 21 fetal HSCs with accessible chromatin after 12 to 14 weeks of gestation.

Journal reference: