Severe Congenital Neutropenia (SCN) is characterized as a deficiency of mature neutrophils, which leads to recurrent bacterial and fungal infections. Mutations in the Ela2 gene predominate in SCN, but Ela2 mutation in mice does not recapitulate SCN. The Growth factor independent-1 (Gfi1) transcriptional repressor regulates Ela2. The N382S mutation in Gfi1 is associated with human SCN. Unlike Ela2, genetic deletion of Gfi1 results in murine neutropenia. Here we show that the human-SCN-associated Gfi1N382S mutant blocks murine granulopoiesis in a Csf1 dependent manner. Gfi1 functions as a rate-limiting granulopoietic molecular switch, and the DNA-binding-defective Gfi1N382S mutant acts as a dominant negative to block granulopoiesis by selectively derepressing a subset of Gfi1 target genes. One gene repressed by Gfi1 and derepressed by Gfi1N382S is the macrophage colony stimulating factor (Csf1). Chromatin immunoprecipitation and electrophoretic mobility shift analyses demonstrate direct binding of Gfi1 to the Csf1 promoter. Importantly, both antibody absorption of Csf1 and genetic deletion of Csf1 prevent the Gfi1N382S-mediated block to granulopoiesis. These data represent the first identified Gfi1 target gene to be critically required for SCN-like phenotypes engendered by Gfi1N382S, and suggest new potential treatment avenues for Gfi1-mutant SCN patients.

Author notes

Disclosure: No relevant conflicts of interest to declare.