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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4181-4190.
Prepublished online as a Blood First Edition Paper on January 23, 2007; DOI 10.1182/blood-2005-05-022004.
 Previous Article | Next Article 
Submitted May 25, 2005
Accepted January 15, 2007
Growth factor independence 1 (Gfi-1) plays a role in
mediating specific granule deficinecy (SGD) in a patient
lacking a gene inactivating mutation in the C/EBP gene
Arati Khanna-Gupta, Hong Sun, Theresa Zibello, Han Myung Lee, Richard Dahl, Laurence A Boxer, and Nancy Berliner*
Section of Hematology, Yale University School of Medicine, New Haven, CT, United States
University of New Mexico Cancer Research Facility, Albuquerque, NM, United States
Division of Pediatric Hematology/Oncology, University of Michigan School of Medicine, Ann Arbor, MI, United States
* Corresponding author; email: nancy.berliner{at}yale.edu.
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/EBP gene have been identified in two SGD patients. Our studies on a third SGD patient revealed a heterozygous mutation in the C/EBP gene. However, we demonstrate elevated levels of C/EBP and PU.1 proteins in the patients peripheral blood neutrophils. The expression of the transcription factor Gfi-1 (Growth factor independent-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/EBP 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 +/+ 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 upregulates the promoter of neutrophil collagenase (an SGP gene), in cooperation with wild type, but not with mutant C/EBP. We hypothesize that decreased Gfi-1 levels in our SGD patient together with the mutant C/EBP, block SGP expression, thereby contributing to the underlying etiology of the disease in our patient.
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