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Unusually for a childhood leukaemia, ML-DS arises from a preleukaemic state, termed transient abnormal myelopoiesis (TAM), via a conserved sequence of mutations. Here, we examine the relationship between the genetic and transcriptional evolution of ML-DS from natural variation; a rich collection of primary patient samples and foetal tissues with a range of constitutional karyotypes. We distil transcriptional consequences of each genetic step in ML-DS evolution, utilising single-cell mRNA sequencing, complemented by phylogenetic analyses in progressive disease. We find that transcriptional changes induced by the TAM-defining\n                    <jats:italic>GATA1<\/jats:italic>\n                    mutations are retained in, and account for most of the ML-DS transcriptome. The\n                    <jats:italic>GATA1<\/jats:italic>\n                    transcriptome pervades 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 distiling consequences of mutations within their pathophysiological context.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-71707-2","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T09:01:45Z","timestamp":1776934905000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Single cell transcriptional evolution of myeloid leukemia of Down syndrome"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4185-0071","authenticated-orcid":false,"given":"Mi 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