2004 Volume 18 Issue 3 Pages 117-126
Children with Down's syndrome have an approximately 20-fold higher incidence of leukemia than unaffected children. The majority of leukemia cases associated with Down's syndrome are acute megakaryocytic leukemia (AMKL). Recently, we and others have demonstrated that mutagenesis of the GATA-1 gene, encoding the erythroid/megakaryocytic transcription factor GATA-1, is a very early event in the development of Down's syndrome-related AMKL (DS-AMKL) in the process of multi-step leukemogenesis. Acquired mutations of the GATA-1 gene have been detected in almost all cases in DS-AMKL and transient myeloproliferative disorder (TMD), “a preleukemia” that may be present in as many as 10% of newborn infants with Down's syndrome. In each, the mutation resulted in the introduction of a premature stop codon in the gene sequence that encodes the N-terminal activation domain and a complete lack of expression of the 50-kD full length GATA-1 protein. Instead, an alternative 40-1W translation product of GATA-1 was expressed from a downstream initiation site. Human tumors have been shown to progress by the accumulation of genetic abnormalities. DS-AMKL is an excellent model of cancer pathogenesis. To understand the mechanisms of a lineage-specific malignant conversion further, it is very important to define the mechanism that results in the high frequency of GATA-1 mutations in Down's syndrome, and to identify the gene or genes on chromosome 21 which cooperate with mutated GATA-1, as well as additional genetic changes in TMD blast cells during the development of DS-AMKL.