Severe congenital neutropenia and chronic neutrophilic leukemia: an intriguing molecular connection unveiled by oncogenic mutations in CSF3R.

Acquired mutations in the colony-stimulating factor 3 receptor gene (CSF3R), truncating the cytosolic region of the CSF3R protein, were discovered almost two decades ago in severe congenital neutropenia (SCN) patients receiving CSF3 treatment to alleviate neutropenia. These CSF3Rmutations are thought to drive clonal expansion by overriding CSF3 hypo-responsiveness of hematopoietic stem and progenitor cells (HSPCs) and are associated with leukemic progression in SCN patients. Furthermore, malignant transformation in one SCN patient coincided with acquisition of an additional auto-activating CSF3Rmutation, supporting the hypothesis that perturbed CSF3 signaling contributes to leukemic transformation of SCN. While acquisition of CSF3R mutations had so far mainly been observed in SCN patients receiving CSF3 therapy, Maxson and colleagues discovered that both truncating and auto-activating CSF3R mutations are frequently present in chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). Furthermore, this study provided preliminary evidence for clinical utility of tyrosine kinase inhibitors (e.g. dasatinib or ruxolitinib) to eradicate CSF3R mutant clones. Here, we discuss the biological and clinical significance of these new findings in the light of the unanticipated and intriguing connection between SCN and aCML/CNL, diseases that are respectively characterized by a severe paucity or an excess of neutrophils.