Single cell transcriptional evolution of myeloid leukemia of Down Syndrome

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukaemia (ML-DS). Unusually for a childhood leukaemia, ML-DS arises from a preleukaemic state (TAM), via a conserved sequence of mutations. In this study, we examined the relationship between the genetic and transcriptional evolution of ML-DS from natural variation. We distilled transcriptional consequences of each genetic step in ML-DS evolution, utilising single cell mRNA sequencing, complemented by phylogenetic analyses in progressive disease. We found that transcriptional changes induced by the TAM-defining GATA1 mutations are retained in, and account for most of the ML-DS transcriptome. The GATA1 transcriptome pervaded all stages of ML-DS, including progressive disease that had undergone genetic evolution. Our approach delineates the transcriptional evolution of ML-DS and provides an analytical blueprint for distilling consequences of mutations within their pathophysiological context.

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Mi K. Trinh, et al. Single cell transcriptional evolution of myeloid leukaemia of Down syndrome. bioRxiv. 2025. https://doi.org/10.1101/2025.04.01.646181