Distinct role of MYC and E2F pathways in developing ML-DS. Simplified model showing the proposed role of MYC and E2F in developing ML-DS. In normal fetal hematopoiesis in the liver (A), GATA1 and RUNX1C inhibit MYC and E2F pathways. In cells with trisomy 21 and a GATA1 mutation, shortened GATA1s and RUNX1A bias fail to repress MYC and E2F, leading to TAM. After birth in the bone marrow (B), additional mutations are needed for uncontrolled MYC and E2F activation. Sato et al show that RUNX1-PTD and the disabling mutation in IRX1 and ZBTB7A can cause MYC and E2F activation, resulting in ML-DS. The figure was created with BioRender.com.