Journal Article

DKFZ-2026-00972

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Single cell transcriptional evolution of myeloid leukemia of Down syndrome.

Trinh, M. K. ; Schuschel, K. ; Issa, H. ; Thomas, R. ; Parks, C. ; Oszlanczi, A. ; Ogbonnah, T. ; Zhou, D. ; Mamanova, L. ; Prigmore, E. ; Robertson, E. R. ; Hodder, A. ; Wenger, A. ; Anderson, N. D. ; Whitfield, H. J. ; Treger, T. D. ; Gonçalves-Dias, J. ; Straathof, K. ; O'Connor, D. ; Young, M. D. ; Jardine, L. ; Adams, S. ; Klusmann, J.-H.DKFZ* ; Bartram, J. ; Behjati, S.

2026
Springer Nature [London]

Abstract: 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.

Keyword(s): Down Syndrome: genetics (MeSH) ; Down Syndrome: complications (MeSH) ; Humans (MeSH) ; GATA1 Transcription Factor: genetics (MeSH) ; Mutation (MeSH) ; Single-Cell Analysis: methods (MeSH) ; Leukemia, Myeloid: genetics (MeSH) ; Leukemia, Myeloid: pathology (MeSH) ; Evolution, Molecular (MeSH) ; Transcriptome: genetics (MeSH) ; Phylogeny (MeSH) ; Leukemoid Reaction: genetics (MeSH) ; Male (MeSH) ; Child (MeSH) ; Female (MeSH) ; Transcription, Genetic (MeSH) ; GATA1 Transcription Factor ; GATA1 protein, human

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Frankfurt (FM01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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