JAK2 and trisomy 21: Trisomy 21 represents a “primary hit”, which alters hematopoiesis during embryonic development; acquisition of somatic GATA1s mutations represents a “secondary hit”, which promotes hematopoietic deregulation and emergence of TAM in DS newborns; additional mutations predominantly affecting chromatin and epigenetic regulators (e.g., the cohesin complex) and signaling mediators (e.g., Janus kinase 2, JAK2) represent a “tertiary hit”, which leads to ML-DS (Labuhn et al., 2019; Garnett et al., 2020; De Castro et al., 2021) (Figure 1).