Down syndrome and leukemia: A model of leukemogenesis and cure

Down syndrome (DS) children with leukemia represent a paradigm in understanding the etiology and therapy of leukemia. DS children have an estimated 10-20-fold higher risk for developing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) compared with non-DS children. DS children with AML display unique features compared with non-DS children, including: (i) a 500- fold increased risk of developing the AML subtype, acute megakaryocytic leukemia (AMkL; M7); (ii) diagnosis of a variant of AMkL, known as the transient myeloproliferative disorder (TMD), in similar to 10% of DS newborns, which can resolve spontaneously without treatment; (iii) event-free survival (EFS) ranging from 80%-100% in comparison with <30% for non-DS children with AMkL; and (iv) uniform detection of somatic mutations in the transcription factor GATA1 gene. The GATA1 mutations are present essentially in 100% of DS AMkL and TMD cases but not in non-DS children with AML, and are key factors linked to both leukemogenesis and high cure rates of DS AMkL patients. GATA1 mutations are not detected in DS ALL cases, although similar to 20% harbor somatic mutations in the JAK2 gene. DS children with ALL have frequently experienced more treatment-related toxicity and inferior EFS rates compared with non-DS children with ALL. Ongoing studies examining leukemogenesis in DS children may identify factors linked to the development of leukemia in children, overall. Further, identifying the mechanisms accounting for the high EFS rates of DS children with AMkL may ultimately be applied to improve the treatment of AML.