Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update

Abstract

Children with constitutional trisomy 21 (Down syndrome (DS)) have a unique predisposition to develop myeloid leukaemia of Down syndrome (ML-DS). This disorder is preceded by a transient neonatal preleukaemic syndrome, transient abnormal myelopoiesis (TAM). TAM and ML-DS are caused by co-operation between trisomy 21, which itself perturbs fetal haematopoiesis and acquired mutations in the key haematopoietic transcription factor gene GATA1. These mutations are found in almost one third of DS neonates and are frequently clinically and haematologcially 'silent'. While the majority of cases of TAM undergo spontaneous remission, ∼10 % will progress to ML-DS by acquiring transforming mutations in additional oncogenes. Recent advances in the unique biological, cytogenetic and molecular characteristics of TAM and ML-DS are reviewed here.

Keywords: Acute leukaemia; Down syndrome; Myeloproliferative disorders; Transient abnormal myelopoiesis.

Fig. 1

Natural history and pathogenesis of TAM and ML-DS. Schematic representation of molecular, biological and clinical data, indicating that transient abnormal myelopoiesis (TAM) and myeloid leukaemia of Down syndrome (ML-DS) are initiated before birth when fetal liver haematopoietic stem and progenitor cells (HSPC) trisomic for chromosome 21 demonstrate perturbed haematopoiesis with an expansion of megakaryocyte-erythroid progenitors (MEP) and megakaryocytes. These cells subsequently acquire N-terminal truncating GATA1 mutations resulting in TAM in late fetal or early neonatal life. Although most cases of TAM spontaneously and permanently remit (∼90 %) by the age of 6 months, in ∼10 % of cases, additional genetic/epigenetic events lead to further clonal expansion resulting in ML-DS before the age of 5 years