Neutrophil elastase is severely down-regulated in severe congenital neutropenia independent of ELA2 or HAX1 mutations but dependent on LEF-1
Neutrophil elastase is severely down-regulated in severe congenital neutropenia independent of ELA2 or HAX1 mutations but dependent on LEF-1
复制标题
DOI：
10.1182/blood-2008-11-188755
复制
发表时间：
2009-10-01
期刊：
影响因子：
20.3
通讯作者：
Welte, Karl
中科院分区：
文献类型：
--
作者：
Skokowa, Julia;Fobiwe, John Paul;Welte, Karl
严重先天性中性粒细胞减少症（CN）是一种异质性骨髓生成疾病，遵循常染色体显性或常染色体隐性遗传模式。遗传分析表明，大多数患者的ELA 2基因突变。我们已经确定LEF-1作为一个决定性的转录因子在粒细胞生成控制增殖和粒细胞分化的直接激活其靶基因，C/EBP α。在CN患者中，髓系祖细胞中LEF-1和C/EBP α的表达被废除，导致粒细胞生成的成熟停滞。在本研究中，我们证明，ELA 2 mRNA表达的髓系祖细胞和中性粒细胞弹性蛋白酶（NE）的血浆蛋白水平显着降低CN窝藏ELA 2或HAX-1基因突变的患者。ELA 2基因启动子受LEF-1或C/EBP α直接结合的正调控，证实了LEF 1在ELA 2表达减少中的作用。我们发现用LEF-1 cDNA转导造血细胞导致ELA 2/NE合成的上调，而用shRNA抑制LEF-1导致ELA 2/NE水平的显著降低。LEF-1对从2名CN患者分离的CD 34（+）细胞的拯救导致细胞的粒细胞分化，这与功能活性ELA 2/NE水平的增加一致。（血。2009; 114：3044-3051）
Severe congenital neutropenia (CN) is a heterogeneous disorder of myelopoiesis which follows an autosomal dominant or autosomal recessive pattern of inheritance. Genetic analyses indicate mutations in the ELA2 gene in most patients. We have identified LEF-1 as a decisive transcription factor in granulopoiesis controlling proliferation and granulocytic differentiation by direct activation of its target gene, C/EBP alpha. In patients with CN, the expression of LEF-1 and C/EBP alpha was abrogated in myeloid progenitors leading to maturation arrest of granulopoiesis. In the present study we demonstrated that ELA2 mRNA expression in myeloid progenitors and plasma protein levels of neutrophil elastase (NE) were markedly reduced in patients with CN harboring mutations in either ELA2 or HAX-1 genes. The ELA2 gene promoter is positively regulated by the direct binding of LEF-1 or C/EBP alpha, documenting the role of LEF1 in the diminished ELA2 expression. We found that transduction of hematopoietic cells with LEF-1 cDNA resulted in the up-regulation of ELA2/NE synthesis, whereas inhibition of LEF-1 by shRNA led to a marked reduction in the levels of ELA2/NE. LEF-1 rescue of CD34(+) cells isolated from 2 patients with CN resulted in granulocytic differentiation of the cells which was in line with increased levels of functionally active ELA2/NE. (Blood. 2009; 114: 3044-3051)