ADGRE2 (adhesion G protein-coupled receptor E2) is a cell surface receptor that functions as a key regulator of immune cell activation and leukemic progression. The receptor binds chondroitin sulfate moieties on glycosaminoglycan chains and promotes granulocyte chemotaxis, degranulation, and adhesion 1. In macrophages, ADGRE2 stimulates release of inflammatory cytokines including IL-8 and TNF, while in mast cells it regulates degranulation through G protein-coupled signaling 2. ADGRE2 represents an antibody-independent mast cell receptor with emerging roles in allergic disease mechanisms 3. In acute myeloid leukemia (AML), ADGRE2 is highly expressed in leukemic stem cells and associates with poor patient outcomes 4. Mechanistically, ADGRE2 activates phospholipase Cβ/protein kinase C/MEK/ERK signaling to enhance AP1-driven expression of DUSP1, a protein phosphatase that maintains proteostasis via DNAJB1-HSP70 interaction 4. Combined MEK, AP1, and DUSP1 inhibition shows robust therapeutic efficacy in AML xenograft models. Clinically, dual-targeting approaches combining attenuated ADGRE2-CAR with CLEC12A costimulation selectively eliminate AML while minimizing hematopoietic stem cell toxicity 5. Additionally, common ADGRE2 repeat alleles exhibit high blood mosaicism rates, demonstrating somatic instability during aging 6.