CSF3R mutations activate kinase signaling to promote the expansion of neutrophils. CSF3R has an N-terminal extracellular domain comprising an Ig-like domain (dark green) and fibronectin type-III repeats (light green). The T618I and T615A (not shown) mutations in the extracellular domain and the T640N mutation in the transmembrane domain (purple) cause ligand-independent receptor activation. Truncation mutations in the cytoplasmic domain (gray) cause increased cell-surface expression of the receptor. CNL-associated mutations in CSF3R cause activation of downstream kinase signaling pathways, such as the JAK/STAT pathway, ultimately driving neutrophil production. P, phosphorylation.