Fetal Liver-Restricted Leukemic Proliferation Via GATA1s-CSF2RB-MPL Axis In Down Syndrome

Transient abnormal myelopoiesis (TAM) is a human fetal liver leukemia driven by GATA1s mutations and a rare exemplar of a spontaneously resolving cancer when blood formation shifts from liver to bone marrow (BM) during development. We report that upregulated cytokine receptor CSF2RB marks TAM cells because it is a GATA2 target that escapes repression by GATA1s. Pathologically expressed CSF2RB unexpectedly interacts with the TPO receptor (MPL) to prolong JAK-STAT signaling by fetal-liver produced TPO, driving GATA1s-mutant cell expansion. TAM can transform into myeloid leukemia of Down syndrome (ML-DS) upon acquisition of additional mutations. The ML-DS driver CSF2RB A455D forces MPL dimerization resulting in constitutive JAK-STAT activation, bypassing TPO dependence in the fetal-liver niche, thereby enabling proliferation in the BM. Base-editing reversion of another ML-DS JAK-STAT-activating mutation, JAK3 A572V, restores TPO dependence. Collectively, we define a cytokine gate that developmentally restricts GATA1s oncogenic competence, highlighting a therapeutically targetable niche-specific tumor dependency.