Haematopoietic development and leukaemia in <scp>D</scp>own syndrome

<jats:title>Summary</jats:title><jats:p>Children with constitutional trisomy 21 (<jats:styled-content style="fixed-case">cT</jats:styled-content>21, <jats:styled-content style="fixed-case">D</jats:styled-content>own <jats:styled-content style="fixed-case">S</jats:styled-content>yndrome, <jats:styled-content style="fixed-case">DS</jats:styled-content>) are at a higher risk for both myeloid and B‐lymphoid leukaemias. The myeloid leukaemias are often preceded by a transient neonatal pre‐leukaemic 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>‐terminal 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‐third 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‐encoded genes, their role in human leukaemogenesis remains unclear. As c<jats:styled-content style="fixed-case">T</jats:styled-content>21 exists in all embryonic cells, the molecular basis of c<jats:styled-content style="fixed-case">T</jats:styled-content>21‐associated leukaemias probably reflects a complex interaction between deregulated gene expression in haematopoietic cells and the fetal haematopoietic microenvironment in <jats:styled-content style="fixed-case">DS</jats:styled-content>.</jats:p>