Single cell transcriptional evolution of myeloid leukaemia 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.; Hodder, A.; Wenger, A.; Anderson, N. D.; Whitfield, H. J.; Treger, T. D.; Goncalves Dias, J.; Straathof, K.; O'Connor, D.; Young, M. D.; Jardine, L.; Adams, S.; Klusmann, J.-H.; Bartram, J.; Behjati, S.
Show 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 examined the relationship between the genetic and transcriptional evolution of ML-DS from natural variation; a rich collection of primary patient samples and fetal tissues with a range of constitutional karyotypes. 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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