The incidence of leukemia is higher in Down syndrome children than that in the general population, while the risk of solid tumors is significantly reduced in Down syndrome. Recent studies utilizing mouse models have shown that distinct mechanisms caused by the elevated dosage of multiple genes is implicated in the protection from tumor progression depending on the type of solid neoplasm. In contrast, increased incidence of mutation in the several specific genes is reported as a cause of the onset of leukemias. Especially, acquired mutations in the GATA1 gene are associated with leukemogenesis of megakaryoblastic leukemia (AMKL) and transient myeloproliferative disorder (TMD) related to Down syndrome. The mutations are clustered in the region corresponding to the N-terminal domain of GATA1 and result in the production of the short form of GATA1 (GATA1-S), which utilizes Met84 as an alternative translation initiation codon. Efforts producing mouse models of Down TMD and AMKL have been undertaken, as these models seem to provide important insights into the pathogenesis of multistep leukemogenesis. Concomitantly, the function of GATA1 has been examined extensively, and the analyses present a prototype for the study of lineage-restricted transcription factors that play an essential role for the differentiation, proliferation, and apoptosis of erythroid cells, megakaryocytes, mast cells, and eosinophils. In this chapter, we will summarize recent progress in the studies of leukemias that occur in Down syndrome, especially in relation to GATA1 mutations.
Part of the book: Health Problems in Down Syndrome