Origin of leukemia in children with down syndrome

Abstract

Children with Down syndrome (DS) are more likely to develop acute myeloid (AML) or acute lymphoblastic leukemia (ALL). AML in children with DS is initiated during fetal hematopoiesis by somatic mutations of GATA1. Leukemic blasts of ALL in DS contain rearrangements of CRLF2 in more than half of all patients. DS is associated with distinct changes of cell subsets during fetal liver hematopoiesis, of folate/one-carbon metabolism and of cell signaling involving NFAT, TGF and WNT pathways. Possible genetic mechanisms of the increased risk for leukemia in DS include gene dosage imbalance of candidate genes and epigenetic dysregulation of gene expression. Fewer data are available regarding the role of noncell-autonomous risk factors, such as abnormal immune function and exposure to environmental carcinogens, during the development of leukemia in children with DS.