CSF3R – Hereditary Neutrophilia

Heterozygous activating missense mutations in CSF3R affecting the membrane-proximal extracellular domain have been reported in hereditary neutrophilia and chronic neutrophilic leukemia (PMID:23604229). In a cohort of 54 clinically suspected CNL or aCML patients, c.1853C>T (p.Thr618Ile) was detected in 83% (10 of 12) of WHO-defined CNL cases and was absent among 170 patients with primary myelofibrosis or chronic myelomonocytic leukemia (PMID:23604229). No familial segregation data have been reported, and the variant has not been observed in healthy controls.

Mechanistic studies demonstrate that p.Thr618Ile disrupts O-linked glycosylation, promotes ligand-independent receptor dimerization, and drives constitutive JAK-STAT signaling in cellular assays (PMID:24403076). These functional data support a gain-of-function mechanism relevant to neutrophil proliferation.

References

• Leukemia • 2013 • CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia. PMID:23604229
• The Journal of Biological Chemistry • 2014 • Ligand independence of the T618I mutation in the colony-stimulating factor 3 receptor (CSF3R) protein results from loss of O-linked glycosylation and increased receptor dimerization. PMID:24403076

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