Mutations in growth factor independent-1 associated with human neutropenia mock murine granulopoiesis through colony stimulating factor-1

作者：Zarebski Adrian; Velu Chinavenmeni S; Baktula Avinash M; Bourdeau Tristan; Horman Shane R; Basu Sudeep; Bertolone Salvatore J; Horwitz Marshal; Hildeman David A; Trent John O; Grimes H Leighton^*

来源：Immunity, 2008, 28(3): 370-380.

DOI：10.1016/j.immuni.2007.12.020

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 GO results in murine neutropenia. We examined whether human SCN-associated GFI1 N382S 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, Gfil N382S selectively derepressed the monopoietic cytokine CSF1 and its receptor. Gfi1 N382S-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.

• 出版日期2008-3