Glycosylphosphatidylinositol-anchor-deficient mice: Implications for clonal dominance of mutant cells in paroxysmal nocturnal hemoglobinuria
Glycosylphosphatidylinositol-anchor-deficient mice: Implications for clonal dominance of mutant cells in paroxysmal nocturnal hemoglobinuria
复制标题
DOI：
10.1182/blood.v87.9.3600.bloodjournal8793600
复制
发表时间：
1996-05-01
期刊：
影响因子：
20.3
通讯作者：
Takeda, J
中科院分区：
文献类型：
--
作者：
Kawagoe, K;Kitamura, D;Takeda, J
阵发性睡眠性血红蛋白尿症（PNH）是一种获得性造血干细胞疾病，其特征是补体介导的溶血。PNH患者的异常造血细胞缺乏糖基磷脂酰肌醇（GPI）锚定蛋白，并在骨髓和外周血的各种造血谱系中呈克隆性优势。对许多PNH患者的分析表明，X连锁基因PIG - A的体细胞突变是导致PNH中GPI锚定缺陷的原因。PIG - A突变也必定与GPI锚定缺陷（GPI（ - ））血细胞的克隆优势有关，因为在许多患者中两个或更多的PIG - A突变克隆成为优势克隆。然而，仅PIG - A突变是否足以导致克隆优势尚不清楚。为了解决这个问题，我们使用Pig - a（PIG - A的鼠类同源基因）被破坏的胚胎干细胞生成了嵌合小鼠，这些小鼠在GPI锚定蛋白的表面表达方面是嵌合的。此类小鼠造血和非造血组织的嵌合率总是很低，这表明Pig - a被破坏的GPI（ - ）细胞的较高比例对嵌合体具有致死作用。一些嵌合小鼠的外周血中出现了GPI（ - ）细胞。然而，出生后10个月内GPI（ - ）红细胞的百分比并未增加，这意味着仅Pig - a突变不会立即导致GPI（ - ）血细胞的克隆优势；造血环境或克隆自身的另一种病理或生理变化可能是必要的。（C）1996年美国血液学会版权所有
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by complement-mediated hemolysis. Abnormal hematopoietic cells from patients with PNH are deficient in glycosylphosphatidylinositol (GPI)-anchored proteins and clonally dominate various hematopoietic lineages in the bone marrow and the peripheral blood, Analysis of many patients with PNH has showed that somatic mutation in the X-linked gene PIG-A is responsible for the GPI-anchor deficiency in PNH, The PIG-A mutation must also be relevant to the clonal dominance of GPI-anchor deficient (GPI(-)) blood cells because two or more PIG-A mutant clones become dominant in many patients. However, whether the PIG-A mutation alone is sufficient for clonal dominance is not known. To address this question, we generated chimeric mice using Pig-a (the murine homologue of PIG-A) disrupted embryonic stem (ES)cells, in which the animals are chimeric with respect to the surface expression of GPI-anchored proteins. The chimerism of hematopoietic and nonhematopoietic tissues in such mice was always low, suggesting that the higher contribution of Pig-a disrupted GPI(-) cells had a lethal effect on the chimera. GPI(-) cells appeared in the peripheral blood of some of the chimeric mice. However, the percentage of GPI(-) erythrocytes did not increase for 10 months after birth, implying that the Pig-a mutation alone does not immediately cause the clonal dominance of GPI(-) blood cells; another pathologic or physiologic change(s) in the hematopoietic environments or in the clone itself may be necessary. (C) 1996 by The American Society of Hematology.