The impact of trisomy 21 on foetal haematopoiesis

Abstract

The high frequency of a unique neonatal preleukaemic syndrome, transient abnormal myelopoiesis (TAM), and subsequent acute myeloid leukaemia in early childhood in patients with trisomy 21 (Down syndrome) points to a specific role for trisomy 21 in transforming foetal haematopoietic cells. N-terminal truncating mutations in the key haematopoietic transcription factor GATA1 are acquired during foetal life in virtually every case. These mutations are not leukaemogenic in the absence of trisomy 21. In mouse models, deregulated expression of chromosome 21-encoded genes is implicated in leukaemic transformation, but does not recapitulate the effects of trisomy 21 in a human context. Recent work using primary human foetal liver and bone marrow cells, human embryonic stem cells and iPS cells shows that prior to acquisition of GATA1 mutations, trisomy 21 itself alters human foetal haematopoietic stem cell and progenitor cell biology causing multiple abnormalities in myelopoiesis and B-lymphopoiesis. The molecular basis by which trisomy 21 exerts these effects is likely to be extremely complex, to be tissue-specific and lineage-specific and to be dependent on ontogeny-related characteristics of the foetal microenvironment.

Keywords: Acute megakaryoblastic leukaemia; DS; Down syndrome; ES; Foetal liver; HSC; IGF; MEP; MK; ML-DS; MPP; Neonatal leukaemia; TAM; Transient abnormal myelopoiesis; Trisomy 21; acute myeloid leukaemia in Down syndrome; embryonic stem; haematopoietic stem cell; iPS; induced pluripotent stem; insulin-like growth factor; megakaryocyte; megakaryocyte–erythroid progenitor; multipotential progenitor; transient abnormal myelopoiesis.

Figure 1. Impact of trisomy 21 on foetal and post-natal hematopoiesis

Schematic representation of the effect of trisomy 21 (T21) on foetal, neonatal and childhood haematopoiesis. Foetal liver cells trisomic for chromosome 21 demonstrate perturbed haematopoiesis with an expansion of the haematopoietic stem cell compartment (HSC), megakaryocyte (MK)-erythroid progenitors (MEP) and megakaryocytes together with reduced B lymphopoiesis. Interaction of haematopoietic cells with the T21 foetal liver microenvironment may play an important role in initiating or maintaining abnormal foetal haematopoiesis, providing a susceptible HSC/progenitor pool upon which subsequent acquisition of N-terminal truncating GATA1 mutations would have a selective advantage. Expansion of the foetal liver mutant GATA1 HSC/progenitor population results in Transient Abnormal Myelopoiesis (TAM) in late foetal or early neonatal life. Although most cases of TAM resolve spontaneously, up to 30% of cases develop Down syndrome-associated acute myeloid leukaemia (ML-DS) before the age of 5 years as a result of additional genetic/ epigenetic events. Reduced foetal B lymphopoiesis may also underlie the increased susceptibility of children with Down Syndrome (T21) to acute lymphoblastic leukaemia (ALL).