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/EBPε gene

Arati Khanna-Gupta, Hong Sun, Theresa Zibello, Myung Lee Han, Richard Dahl, Laurence A. Boxer, Nancy Berliner

Research output: Contribution to journalArticle

34 Citations (Scopus)

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/EBPε gene have been identified in 2 SGD patients. Our studies on a third SGD patient revealed a heterozygous mutation in the C/EBPε gene. However, we demonstrate elevated levels of C/EBPε 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/EBPε 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/EBPε. We hypothesize that decreased Gfi-1 levels in our SGD patient, together with the mutant C/EBPε, block SGP expression, thereby contributing to the underlying etiology of the disease in our patient.

Original languageEnglish (US)
Pages (from-to)4181-4190
Number of pages10
JournalBlood
Volume109
Issue number10
DOIs
StatePublished - May 15 2007
Externally publishedYes

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Intercellular Signaling Peptides and Proteins
Genes
Mutation
Neutrophils
Proteins
Specific Granule Deficiency
Matrix Metalloproteinase 8
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Bone Development
Bacterial Infections
Gene expression
Bone
Blood
Transcription Factors
Up-Regulation
Bone Marrow
Cells
Gene Expression
Cell Line

ASJC Scopus subject areas

  • Hematology

Cite this

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/EBPε gene. / Khanna-Gupta, Arati; Sun, Hong; Zibello, Theresa; Han, Myung Lee; Dahl, Richard; Boxer, Laurence A.; Berliner, Nancy.

In: Blood, Vol. 109, No. 10, 15.05.2007, p. 4181-4190.

Research output: Contribution to journalArticle

Khanna-Gupta, Arati ; Sun, Hong ; Zibello, Theresa ; Han, Myung Lee ; Dahl, Richard ; Boxer, Laurence A. ; Berliner, Nancy. / 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/EBPε gene. In: Blood. 2007 ; Vol. 109, No. 10. pp. 4181-4190.
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