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Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2


Mice lacking the transcriptional repressor oncoprotein Gfi1 are unexpectedly neutropenic1,2. We therefore screened GFI1 as a candidate for association with neutropenia in affected individuals without mutations in ELA2 (encoding neutrophil elastase), the most common cause of severe congenital neutropenia (SCN; ref. 3). We found dominant negative zinc finger mutations that disable transcriptional repressor activity. The phenotype also includes immunodeficient lymphocytes and production of a circulating population of myeloid cells that appear immature. We show by chromatin immunoprecipitation, gel shift, reporter assays and elevated expression of ELA2 in vivo in neutropenic individuals that GFI1 represses ELA2, linking these two genes in a common pathway involved in myeloid differentiation.

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Figure 1: GFI1 mutations and hematopoietic phenotype.
Figure 2: Transcriptional and DNA-binding consequences of mutations in GFI1.
Figure 3: ChIP assay showing Gfi1 targeting of ELA2.


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We thank P. Tsichlis for reagents and advice, J. Miller for advice, K. Williams for technical assistance and the subjects for their cooperation. M.H. thanks the late D.M. Horwitz for his encouragement and support. This work was supported by the U.S. National Institutes of Health, Doris Duke Foundation, Leukemia & Lymphoma Society and Burroughs-Wellcome grants (M.H.) and Hope Street Kids grant (H.L.G.).

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Correspondence to Marshall Horwitz.

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Person, R., Li, FQ., Duan, Z. et al. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nat Genet 34, 308–312 (2003).

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