Decoding the ontogeny of myeloid lineage diversity by cross-species and developmental analyses of hematopoietic progenitor atlases

Myeloid cells play vital roles in homeostasis and immune responses in vertebrates, but the developmental pathway underlying their lineage diversity remains elusive. Here, we construct a single-cell transcriptional map of myeloid progenitors from mouse bone marrow and conduct cross-species and developmental analyses across human, monkey, mouse, and zebrafish. We uncover a conserved specification program separating the eosinophil-basophil-mast cell (EBM) lineage and neutrophil-monocyte (NM) lineage, reclassifying myeloid cells beyond the conventional granulocytic and monocytic framework. By generating Ikzf2-EGFP reporter mice, we identify IKZF2 as a priming marker for EBM lineage specification. Ikzf2-EGFP⁺ and Ikzf2-EGFP^- granulocyte-monocyte progenitors (GMPs) exhibit distinct potential to generate EBM and NM lineages, and Ikzf2-EGFP expression robustly distinguishes their progenies. Additionally, we demonstrate that lineage specification emerges early during myelopoiesis. These findings provide a redefined perspective on myeloid lineage ontogeny, highlighting the conservation of lineage specification and offering insights into the understanding and therapeutic development of myelopoiesis.