Model of sequential genetic and epigenetic events associated with DS-AMKL development. Two distinct waves of epigenetic reprogramming were detected. The first wave, which happens upon acquisition of an additional copy of chromosome 21, results in genome-wide hypomethylation and affects genes involved in developmental processes. The second wave, detected in DS-TMD blasts, results in hypermethylation of genes involved in hematological disorders and regulation of key cellular processes. No additional epigenetic changes are detected upon progression to DS-AMKL, but DS-AMKL blasts are hypomethylated in comparison with NBM CD34⁺ and non–DS-AMKL blasts.