Several signaling systems downstream of G-CSFR have been identified that are defective or hyperactivated in myeloid cells of patients with congenital neutropenia: severely reduced expression of myeloid-specific transcription factors LEF-1 and C/EBPα, severely reduced expression and functions of HCLS1 protein, severely reduced expression of neutrophil elastase protein, dramatic compensatory up-regulation of the NAMPT/NAD(+)/SIRT pathway leading to continuous activation of emergency granulopoiesis via the transcription factor C/EBPβ, and hyperactivation of STAT5 protein by tyrosine phosphorylation.
Acquired G-CSFR (CSF3R) mutations are detected in approximately 80% of patients who had CN and who developed acute myeloid leukemia, suggesting that these mutations are involved in leukemogenesis.