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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. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2005-05-022004v1 109/10/4181    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Khanna-Gupta, A. Articles by Berliner, N. Search for Related Content PubMed PubMed Citation Articles by Khanna-Gupta, A. Articles by Berliner, N. Related Collections Hematopoiesis and Stem Cells Phagocytes Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS 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/EBP gene Arati Khanna-Gupta1, Hong Sun1, Theresa Zibello1, Han Myung Lee1, Richard Dahl2, Laurence A. Boxer3, and Nancy Berliner1 1 Section of Hematology, Yale University School of Medicine, New Haven, CT; 2 University of New Mexico, Cancer Research Facility, Albuquerque; 3 Division of Pediatric, Hematology/Oncology, University of Michigan School of Medicine, Ann Arbor 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 2 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 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/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 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/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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. J. Salipante, M. E. B. Rojas, B. Korkmaz, Z. Duan, J. Wechsler, K. F. Benson, R. E. Person, H. L. Grimes, and M. S. Horwitz Contributions to Neutropenia from PFAAP5 (N4BP2L2), a Novel Protein Mediating Transcriptional Repressor Cooperation between Gfi1 and Neutrophil Elastase Mol. Cell. Biol., August 15, 2009; 29(16): 4394 - 4405. [Abstract] [Full Text] [PDF] J. Karlsson, G. Carlsson, O. Larne, M. Andersson, and K. Putsep Vitamin D3 induces pro-LL-37 expression in myeloid precursors from patients with severe congenital neutropenia J. Leukoc. Biol., November 1, 2008; 84(5): 1279 - 1286. [Abstract] [Full Text] [PDF] D. C. Dale, L. Boxer, and W. C. Liles The phagocytes: neutrophils and monocytes Blood, August 15, 2008; 112(4): 935 - 945. [Abstract] [Full Text] [PDF] Z. Duan, R. E. Person, H.-H. Lee, S. Huang, J. Donadieu, R. Badolato, H. L. Grimes, T. Papayannopoulou, and M. S. Horwitz Epigenetic Regulation of Protein-Coding and MicroRNA Genes by the Gfi1-Interacting Tumor Suppressor PRDM5 Mol. Cell. Biol., October 1, 2007; 27(19): 6889 - 6902. [Abstract] [Full Text] [PDF]

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