Model for the progression of TMD and AMKL in DS. Trisomy 21 likely represents the initiating event in leukemogenesis of DS because it occurs very early in embryogenesis. The subsequent mutagenesis of GATA1 and selection of progenitor cells that harbor GATA1 mutations may be the second initiating event that leads to the neonatal appearance of TMD in at least 10% of infants with DS. In the majority of infants with TMD, the GATA1 mutant clones disappear during remission, but 30% of the time, the mutant clones acquire additional mutations that promote the development of acute leukemia by the age of 4 years.