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

Abstract Some childhood cancers can arise in utero and then regress at birth, but the cues that permit malignant proliferation in utero as opposed to postnatal life are often unclear. 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. Here we show that the cytokine receptor CSF2RB is aberrantly upregulated in TAM cells because it is a GATA2 target that escapes repression by GATA1s. Pathologically expressed CSF2RB unexpectedly interacts with the thrombopoietin receptor MPL to prolong JAK-STAT signaling by fetal-liver produced THPO, driving GATA1s-mutant cell expansion. TAM can transform into myeloid leukemia of Down syndrome (ML-DS) upon acquisition of additional mutations. We further show that the ML-DS driver CSF2RB A455D forces MPL dimerization resulting in constitutive JAK-STAT activation, bypassing THPO dependence in the fetal-liver niche, thereby enabling proliferation in the BM. Conversely, base-editing reversion of another ML-DS JAK-STAT-activating mutation, JAK3 A572V, restores THPO dependence. These results identify a cytokine gate that developmentally restricts GATA1s oncogenic competence, reconciling why TAM expands in the fetal liver yet resolves after birth, revealing a niche-specific, therapeutically targetable dependency.