title: Mutations in growth factor independent-1 associated with human neutropenia block murine granulopoiesis through colony stimulating factor-1.
abstract: Severe congenital neutropenia (SCN) is characterized by a deficiency of mature neutrophils, leading to recurrent bacterial and fungal infections. Although mutations in Elastase-2, neutrophil (ELA2) predominate in human SCN, mutation of Ela2 in mice does not recapitulate SCN. The growth factor independent-1 (GFI1) transcription factor regulates ELA2. Mutations in GFI1 are associated with human SCN, and genetic deletion of Gfi1 results in murine neutropenia. We examined whether human SCN-associated GFI1N382S mutant proteins are causal in SCN and found that GFI1 functions as a rate-limiting granulopoietic molecular switch. The N382S mutation inhibited GFI1 DNA binding and resulted in a dominant-negative block to murine granulopoiesis. Moreover, Gfi1N382S selectively derepressed the monopoietic cytokine CSF1 and its receptor. Gfi1N382S-expressing Csf1-/- cells formed neutrophils. These results reveal a common transcriptional program that underlies both human and murine myelopoiesis, and that is central to the pathogenesis of SCN associated with mutations in GFI1. This shared transcriptional pathway may provide new avenues for understanding SCN caused by mutations in other genes and for clinical intervention into human neutropenias.
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Zarebski
authors.forename: Chinavenmeni S
authors.initials: CS
authors.lastname: Velu
authors.forename: Avinash M
authors.initials: AM
authors.lastname: Baktula
authors.forename: Tristan
authors.initials: T
authors.lastname: Bourdeau
authors.forename: Shane R
authors.initials: SR
authors.lastname: Horman
authors.forename: Sudeep
authors.initials: S
authors.lastname: Basu
authors.forename: Salvatore J
authors.initials: SJ
authors.lastname: Bertolone
authors.forename: Marshal
authors.initials: M
authors.lastname: Horwitz
authors.forename: David A
authors.initials: DA
authors.lastname: Hildeman
authors.forename: John O
authors.initials: JO
authors.lastname: Trent
authors.forename: H Leighton
authors.initials: HL
authors.lastname: Grimes
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D006098:Granulocytes / Q000166:cytology*; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009503:Neutropenia / Q000151:congenital / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; D014157:Transcription Factors; D016173:Macrophage Colony-Stimulating Factor