title: Growth factor independence-1 (Gfi-1) plays a role in mediating specific granule deficiency (SGD) in a patient lacking a gene-inactivating mutation in the C/EBPepsilon gene.
abstract: Neutrophil-specific granule deficiency (SGD) is a rare congenital disorder marked by recurrent bacterial infections. Neutrophils from SGD patients lack secondary and tertiary granules and their content proteins and lack normal neutrophil functions. Gene-inactivating mutations in the C/EBPepsilon gene have been identified in 2 SGD patients. Our studies on a third SGD patient revealed a heterozygous mutation in the C/EBPepsilon gene. However, we demonstrate elevated levels of C/EBPepsilon and PU.1 proteins in the patient's peripheral blood neutrophils. The expression of the transcription factor growth factor independence-1 (Gfi-1), however, was found to be markedly reduced in our SGD patient despite the absence of an obvious mutation in this gene. This may explain the elevated levels of both C/EBPepsilon and PU.1, which are targets of Gfi-1 transcriptional repression. We have generated a growth factor-dependent EML cell line from the bone marrow of Gfi-1(+/-) and Gfi-1(+/+) mice as a model for Gfi-1-deficient SGD, and demonstrate that lower levels of Gfi-1 expression in the Gfi-1(+/-) EML cells is associated with reduced levels of secondary granule protein (SGP) gene expression. Furthermore, we demonstrate a positive role for Gfi-1 in SGP expression, in that Gfi-1 binds to and up-regulates the promoter of neutrophil collagenase (an SGP gene), in cooperation with wild-type but not with mutant C/EBPepsilon. We hypothesize that decreased Gfi-1 levels in our SGD patient, together with the mutant C/EBPepsilon, block SGP expression, thereby contributing to the underlying etiology of the disease in our patient.
authors.affiliation: Section of Hematology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Arati
authors.initials: A
authors.lastname: Khanna-Gupta
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Theresa
authors.initials: T
authors.lastname: Zibello
authors.forename: Han Myung
authors.initials: HM
authors.lastname: Lee
authors.forename: Richard
authors.initials: R
authors.lastname: Dahl
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Boxer
authors.forename: Nancy
authors.initials: N
authors.lastname: Berliner
mesh_terms: D001483:Base Sequence; D001853:Bone Marrow / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D007154:Immune System Diseases / Q000151:congenital* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C498275:GFI1 protein, human; C070790:CEBPE protein, human