MS4A3 is a transmembrane protein that functions as a hematopoietic regulator with distinct roles depending on cellular context. In myeloid differentiation, MS4A3 promotes granulocyte/macrophage lineage commitment and serves as a reliable marker for early myeloid progenitors 1. MS4A3 expression increases progressively during myeloid differentiation while remaining absent in lymphoid and megakaryocytic-erythrocytic lineages 1. Mechanistically, MS4A3 enhances common β-chain cytokine receptor endocytosis upon GM-CSF/IL-3 stimulation, amplifying downstream signaling and promoting cellular differentiation 2. In chr11 myeloid leukemia, leukemic stem/progenitor cells suppress MS4A3 expression through aberrant methylation and transcriptional regulation, enabling them to evade cytokine-induced differentiation and maintain TKI resistance 2. MS4A3 also participates in the MS4A3-HSP27 pathway, regulating erythroid differentiation through HSP27 phosphorylation 3. Beyond hematopoiesis, MS4A3 serves as a fate-mapping marker for granulocyte-monocyte progenitors 4 and tracks peripherally-derived macrophages in brain injury models 5. MS4A3 expression is downregulated during macrophage differentiation 6, suggesting context-dependent regulation. These findings position MS4A3 as a critical regulator of hematopoietic cell fate decisions with therapeutic implications for myeloid malignancies.