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<p>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, 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 <i>GATA1</i> mutations are retained in, and account for most of the ML-DS transcriptome. The <i>GATA1</i> 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.</p>

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Single cell transcriptional evolution of myeloid leukemia of Down syndrome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月23日

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  • Mi K. Trinh,
  • Konstantin Schuschel,
  • Hasan Issa,
  • Rebecca Thomas,
  • Conor Parks,
  • Agnes Oszlanczi,
  • Toochi Ogbonnah,
  • Di Zhou,
  • Lira Mamanova,
  • Elena Prigmore,
  • Emilia R. Robertson,
  • Angus Hodder,
  • Anna Wenger,
  • Nathaniel D. Anderson,
  • Holly J. Whitfield,
  • Taryn D. Treger,
  • José Gonçalves-Dias,
  • Karin Straathof,
  • David O’Connor,
  • Matthew D. Young,
  • Laura Jardine,
  • Stuart Adams,
  • Jan-Henning Klusmann,
  • Jack Bartram,
  • Sam Behjati

摘要

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, 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 GATA1 mutations are retained in, and account for most of the ML-DS transcriptome. The GATA1 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.