One of the earliest identified risk factors for childhood leukemia was Down syndrome (DS). Children with DS, who are born with an extra copy of chromosome 21 (i.e. trisomy 21), have an ~20-fold increased risk of developing B-cell acute lymphoblastic leukemia (B-ALL) and ~500-fold risk of acute megakaryoblastic leukemia (AMKL, which is usually very rare in the general population). Experimental studies have shown that trisomy 21 affects the normal development of blood cells.
Analysis of the effects of trisomy 21 on fetal hematopoiesis revealed impaired B-cell differentiation, and increased frequency and clonogenicity of hematopoietic stem cells (PMID:23045701). Moreover, experiments in mice have shown that triplication of 31 genes, in a region orthologous to the Down syndrome “critical region” on chromosome 21 in humans, led to genome-wide epigenetic effects and, importantly, increased self-renewal and proliferation of early B-cells (PMID:24747640). Children with DS also have dysregulated immune systems and are more prone to infections, which may contribute to their increased leukemia risk. Still, only ~1% of children with DS will develop ALL, suggesting a role for additional genetic and non-genetic risk factors in modifying disease risk.
To investigate genetic and environmental risk factors for Down syndrome ALL (DS-ALL) we initiated a global collaboration, the International Study of Down Syndrome Acute Leukemia (IS-DSAL), funded by Alex’s Lemonade Stand Foundation (https://www.alexslemonade.org/grantee/adam-de-smith-phd). We have collected DNA from over 250 DS-ALL patients from studies across Europe and the Americas, and also obtained samples from DS children who did not develop leukemia.
In collaboration with a Children’s Oncology Group study of DS-ALL (led by Drs. Karen Rabin and Philip Lupo, Baylor College of Medicine), we published the first GWAS of DS-ALL which discovered a higher penetrance of some known ALL risk variants in the context of trisomy 21 (PMID: 31350265). We have subsequently published the first exome-sequencing study in DS-ALL (PMID: 32084258) and the first epigenome-wide association study of DS-ALL (PMID: 35588500).
We have also analyzed genome-wide DNA methylation array data from newborns with and without trisomy 21, revealing over 1,000 differentially methylated regions and identifying the hematopoietic transcription factors RUNX1 and FLI1 as the most significantly differentially methylated genes in Down syndrome (PMID: 33547282).
Our studies of DS-ALL may also reveal factors that contribute to ALL risk in the non-DS population.