IL3R

IL3R, or the interleukin-3 receptor, is a cytokine receptor that binds interleukin-3. It functions as a heteromeric receptor comprising a ligand-specific alpha chain (IL3RA, also known as CD123) and a common beta chain (CSF2RB) shared with the receptors for IL-5 and GM-CSF. The alpha chain determines ligand binding, while the beta chain mediates signal transduction.

Upon IL-3 binding, the receptor activates intracellular signaling cascades, notably the JAK2-STAT5 axis, and also engages MAPK and PI3K pathways, promoting cellular proliferation, survival, and differentiation in hematopoietic cells.

IL3RA/CD123 is expressed on hematopoietic stem and progenitor cells, basophils, plasmacytoid dendritic cells, and certain leukemic cells. In healthy individuals, expression is highest on early myeloid progenitors and some dendritic cell subsets. In malignancies such as acute myeloid leukemia, acute lymphoblastic leukemia, and blastic plasmacytoid dendritic cell neoplasm (BPDCN), CD123 is often overexpressed and used as a diagnostic marker and, increasingly, as a therapeutic target.

Clinical relevance is underscored by therapies targeting CD123. Tagraxofusp (also known as SL-401), a CD123-directed cytotoxin fusion protein, is approved for BPDCN and is being investigated in AML and other hematologic malignancies. Other approaches include anti-CD123 monoclonal antibodies, bispecific engagers, and CD123-directed CAR-T cell therapies. Potential challenges include off-target effects and cytokine-release risks.