Haematopoietic development and leukaemia in Down syndrome

Summary Children with constitutional trisomy 21 ( cT 21, D own S yndrome, DS ) 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, T ransient A bnormal M yelopoiesis ( TAM ). TAM is caused by cooperation between c T 21 and acquired somatic N ‐terminal truncating mutations in the key haematopoietic transcription factor GATA 1 . These mutations, which are not leukaemogenic in the absence of c T 21, are found in almost one‐third of neonates with DS . Analysis of primary human fetal liver haematopoietic cells and of human embryonic stem cells demonstrates that c T 21 itself substantially alters human fetal haematopoietic development. Consequently, many haematopoietic developmental defects are observed in neonates with DS even in the absence of TAM . 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 T 21 exists in all embryonic cells, the molecular basis of c T 21‐associated leukaemias probably reflects a complex interaction between deregulated gene expression in haematopoietic cells and the fetal haematopoietic microenvironment in DS .