CSF3R

The colony-stimulating factor 3 receptor (CSF3R), also known as granulocyte colony-stimulating factor receptor (G-CSFR), is a transmembrane cytokine receptor critical for neutrophil production and function. It binds G-CSF to activate JAK-STAT, PI3K/AKT, and MAPK signaling pathways, regulating myeloid cell proliferation, differentiation, and survival. Germline CSF3R mutations cause severe congenital neutropenia (SCN), while acquired mutations (e.g., truncations like T618I) are hallmark drivers of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML), often promoting leukemogenesis through constitutive JAK-STAT activation. Dysregulated CSF3R signaling also correlates with chemotherapy resistance and inflammatory disorders. Targeted therapies include JAK inhibitors (ruxolitinib) and selective CSF3R antagonists (e.g., momelotinib), with ongoing trials exploring mutant-specific inhibitors and combination regimens for myeloid malignancies. Diagnostic CSF3R mutation screening is now standard for CNL classification per WHO guidelines.