Down syndrome and leukemia: insights into leukemogenesis and translational targets

• Published in: Translational pediatrics 2015-04, Vol.4 (2), p.76-92
• Main Authors: Mateos, Marion K, Barbaric, Draga, Byatt, Sally-Anne, Sutton, Rosemary, Marshall, Glenn M
• Format: Article
• Language: English
• Subjects: Review
• ISSN: 2224-4344; 2224-4344
• DOI: 10.3978/j.issn.2224-4336.2015.03.03

Children with Down syndrome (DS) have a significantly increased risk of childhood leukemia, in particular acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (DS-ALL). A pre-leukemia, called transient myeloproliferative disorder (TMD), characterised by a GATA binding protein 1 (GATA1) mutation, affects up to 30% of newborns with DS. In most cases, the pre-leukemia regresses spontaneously, however one-quarter of these children will go on to develop AMKL or myelodysplastic syndrome (MDS) . AMKL and MDS occurring in young children with DS and a GATA1 somatic mutation are collectively termed myeloid leukemia of Down syndrome (ML-DS). This model represents an important multi-step process of leukemogenesis, and further study is required to identify therapeutic targets to potentially prevent development of leukemia. DS-ALL is a high-risk leukemia and mutations in the JAK-STAT pathway are frequently observed. JAK inhibitors may improve outcome for this type of leukemia. Genetic and epigenetic studies have revealed likely candidate drivers involved in development of ML-DS and DS-ALL. Overall this review aims to identify potential impacts of new research on how we manage children with DS, pre-leukemia and leukemia.