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
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
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DOI：
10.1182/blood-2005-05-022004
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发表时间：
2007-05-15
期刊：
影响因子：
20.3
通讯作者：
Berliner, Nancy
中科院分区：
文献类型：
--
作者：
Khanna-Gupta, Arati;Sun, Hong;Berliner, Nancy
嗜中性粒细胞特异性颗粒缺乏症（SGD）是一种罕见的先天性疾病，其特征是反复发生细菌感染。来自SGD患者的中性粒细胞缺乏二级和三级颗粒及其内含物蛋白，并且缺乏正常的中性粒细胞功能。在2例SGD患者中发现了C/EBP β基因的基因失活突变。我们对第三例SGD患者的研究显示C/EBP β基因存在杂合突变。然而，我们证明了患者外周血中性粒细胞中C/EBP β和PU.1蛋白水平升高。转录因子生长因子独立性-1（Gfi-1）的表达，然而，被发现在我们的SGD患者显着减少，尽管在这个基因中没有一个明显的突变。这可能解释了C/EBP β和PU.1的水平升高，它们是Gfi-1转录抑制的靶点。我们已经从Gfi-1（+/-）和Gfi-1（+/+）小鼠的骨髓中产生了生长因子依赖性EML细胞系作为Gfi-1缺陷型SGD的模型，并证明Gfi-1（+/-）EML细胞中较低水平的Gfi-1表达与次级颗粒蛋白（SGP）基因表达水平的降低相关。此外，我们证明了Gfi-1在SGP表达中的积极作用，因为Gfi-1结合并上调中性粒细胞胶原酶（SGP基因）的启动子，与野生型合作，但不与突变型C/EBP β。我们推测，在我们的SGD患者中，Gfi-1水平降低，连同突变的C/EBP β，阻断SGP表达，从而导致我们患者的疾病的潜在病因。
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 epsilon gene have been identified in 2 SGD patients. Our studies on a third SGD patient revealed a heterozygous mutation in the C/EBP epsilon gene. However, we demonstrate elevated levels of C/EBP epsilon 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 epsilon 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 epsilon. We hypothesize that decreased Gfi-1 levels in our SGD patient, together with the mutant C/EBP epsilon, block SGP expression, thereby contributing to the underlying etiology of the disease in our patient.