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The myeloid leukaemias are often preceded by a transient neonatal pre\u2010leukaemic syndrome, <jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>ransient <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>bnormal <jats:styled-content style=\"fixed-case\">M<\/jats:styled-content>yelopoiesis (<jats:styled-content style=\"fixed-case\">TAM<\/jats:styled-content>). <jats:styled-content style=\"fixed-case\">TAM<\/jats:styled-content> is caused by cooperation between c<jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>21 and acquired somatic <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>\u2010terminal truncating mutations in the key haematopoietic transcription factor <jats:italic><jats:styled-content style=\"fixed-case\">GATA<\/jats:styled-content>1<\/jats:italic>. These mutations, which are not leukaemogenic in the absence of c<jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>21, are found in almost one\u2010third of neonates with <jats:styled-content style=\"fixed-case\">DS<\/jats:styled-content>. Analysis of primary human fetal liver haematopoietic cells and of human embryonic stem cells demonstrates that c<jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>21 itself substantially alters human fetal haematopoietic development. Consequently, many haematopoietic developmental defects are observed in neonates with <jats:styled-content style=\"fixed-case\">DS<\/jats:styled-content> even in the absence of <jats:styled-content style=\"fixed-case\">TAM<\/jats:styled-content>. Although studies in mouse models have suggested a pathogenic role of deregulated expression of several chromosome 21\u2010encoded genes, their role in human leukaemogenesis remains unclear. 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