Irene Roberts

Key Points: GATA1 mutations are common in neonates with Down syndrome but are often unsuspected and detectable only with sensitive methods. Multilineage blood abnormalities in all Down syndrome neonates in the absence of GATA1 mutations suggests that trisomy 21 itself perturbs hemopoiesis.

(2013). The impact of trisomy 21 on early human hematopoiesis. Cell Cycle: Vol. 12, No. 4, pp. 533-534.

The 40-fold increase in childhood megakaryocyte-erythroid and B-cell leukemia in Down syndrome implicates trisomy 21 (T21) in perturbing fetal hematopoiesis. Here, we show that compared with primary disomic controls, primary T21 fetal liver (FL) hematopoietic stem cells (HSC) and megakaryocyte-erythroid progenitors are markedly increased, whereas granulocyte-macrophage progenitors are reduced. Commensurately, HSC and megakaryocyte-erythroid progenitors show higher clonogenicity, with increased megakaryocyte, megakaryocyte-erythroid, and replatable blast colonies. Biased megakaryocyte-erythroid–primed gene expression was detected as early as the HSC compartment. In lymphopoiesis, T21 FL lymphoid-primed multipotential progenitors and early lymphoid progenitor numbers are maintained, but there was a 10-fold reduction in committed PreproB-lymphoid progenitors and the functional B-cell potential of HSC and early lymphoid progenitor is severely impaired, in tandem with reduced early lymphoid gene expression. The same pattern was seen in all T21 FL samples and no samples had GATA1 mutations. Therefore, T21 itself causes multiple distinct defects in FL myelo- and lymphopoiesis.

Summary: Although neonatal thrombocytopenia (platelet count < 150 × 10⁹/l) is a common finding in hospital practice, a careful clinical history and examination of the blood film is often sufficient to establish the diagnosis and guide management without the need for further investigations. In preterm neonates, early‐onset thrombocytopenia (72 h) is nearly always due to post‐natally acquired bacterial infection and/or necrotizing enterocolitis, which rapidly leads to severe thrombocytopenia (platelet count < 50 × 10⁹/l). Thrombocytopenia is much less common in term neonates and the most important cause is neonatal alloimmune thrombocytopenia (NAIT), which confers a high risk of perinatal intracranial haemorrhage and long‐term neurological disability. Prompt diagnosis and transfusion of human platelet antigen‐compatible platelets is key to the successful management of NAIT. Recent studies suggest that more than half of neonates with severe thrombocytopenia receive platelet transfusion(s) based on consensus national or local guidelines despite little evidence of benefit. The most pressing problem in management of neonatal thrombocytopenia is identification of safe, effective platelet transfusion therapy and controlled trials are urgently needed.

Was Hippocrates aware when he insisted that physicians primum non nocere (first, do no harm) that this precept would still prove challenging to his colleagues 2000 years later? In his day, diseases were probably diagnosed only in the presence of overt symptoms, and asymptomatic children were no

Summary: Children with Down syndrome (DS) have a marked increase in susceptibility to Acute Megakaryoblastic Leukaemia (DS‐AMKL) and the closely linked neonatal preleukaemic syndrome, Transient Myeloproliferative Disorder (DS‐TMD). The distinct stages of DS‐TMD and DS‐AMKL provide an excellent tractable model to study leukaemogenesis. This review focuses on recent studies describing clinical, haematological and biological features of DS‐AMKL and DS‐TMD. The findings from these studies suggest that mutations in the key haemopoietic regulator GATA1 (GATA binding protein 1) in DS‐AMKL and DS‐TMD may be useful in diagnosis and assessing minimal residual disease. These findings raise the possibility of population‐based screening strategies for DS‐TMD and the development of treatment to eliminate the preleukaemic TMD clone to prevent DS‐AMKL. Advances in our understanding of perturbed haemopoiesis in DS, the role of GATA1 and of cooperating mutations are also discussed. These findings have implications for leukaemia biology more broadly given the frequency of acquired trisomy in other human leukaemias.