Schematic of the combined effects of trisomy 21 and GATA-1s mutations on the pathogenesis of DS-TMD (preleukemia) and the progression to leukemia. Left panel, in normal FL HSPCs, the transcription factor ARID3A functionally cooperates with full length GATA 1 to induce normal MK proliferation and differentiation. Right panel, in FL HSCs isolated from fetuses with trisomy 21 (T21), 3 chromosome 21 miRNAs are upregulated: miR-99a, miR-155, and miR-125b. The elevated miR125b levels posttranscriptionally repress ARID3A. The combination of low ARID3A levels and GATA-1s in T21 fetuses carrying GATA1s mutations leads to MK hyperproliferation and maturational arrest, which characterize DS-TMD (preleukemia). The progression from preleukemia to leukemia requires additional mutations, most frequently in the cohesin genes STAG2, RAD21, and NIPBL. CD117 (KIT) is a marker of the cells that mediate the propagation of GATA1s-induced preleukemia and GATA1s/STAG2ko-induced leukemia. ARID3A and CD117 (KIT) are potential therapeutic targets for DS-TMD and to avoid the progression to leukemia. Professional illustration by Somersault 18:24.