GATA1 mutations in a cohort of Malaysian children with Down syndrome-associated myeloid disorder

Down syndrome (DS) is the most common congenital cytogenetic abnormality, with an incidence of one in 600-800 live births. he syndrome is characterised by recognisable physical features, cognitive disability, and a varying frequency of cardiac, gastrointestinal, skeletal and endocrine defects. DS is also characterised by an increased susceptibility to childhood leukaemia, A spontaneously resolving congenital myeloproliferative state designated as transient abnormal myelopoiesis (TAM) is encountered in 10%-20% of DS newborns. After a period of apparent remission (1-4 years), 20%-30% of DS children with TAM progress to develop a characteristic, treatment-responsive megakaryoblastic form of acute myeloid leukaemia termed myeloid leukaemia of DS (ML-DS). AM and ML-DS thus represent a continuum of clonal myeloproliferation in DS. Fundamental to both disorders is the gene-dosage imbalance of the human chromosome 21. n additional shared, critical pathogenetic event involves the acquisition of characteristic somatic mutations in the GATA1 gene. The gene, located on chromosome X (Xp11.23), encodes a key haematopoietic transcription factor involved in erythroid and megakaryocyte differentiation. These mutations, involving exons 2 or 3 of the GATA1 gene, result in synthesis of an aberrant truncated isoform (termed short GATA1 or GATA1s) that is putatively oncogenic. The mechanistic basis for somatic GATA1 mutations and the additional molecular events that determine progression from TAM to ML-DS are the focus of intense research. his observational study attempts to characterise, for the first time, to our knowledge, the frequency and nature of somatic GATA1 mutations in DS children with TAM and ML-DS, encountered consecutively over a period of five years at a national paediatric oncology referral centre in Malaysia.