Molecular Mechanisms for the clonal expansion of abnormal cells in hematopoietic stem cell disorders

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，其特征是糖基磷脂酰肌醇（GPI）缺陷细胞的克隆扩增，导致补体介导的溶血。一些证据表明，PIGA的体细胞突变和额外的异常是必要的突变克隆的克隆扩增。我们提出了PNH中GPI缺陷型造血干细胞克隆扩增的三步模型。PIG-A的体细胞突变发生在造血干细胞中，导致所有GPI锚定蛋白的表面表达缺陷（步骤1）。对造血干细胞的免疫攻击减少了干细胞的数量，积极选择GPI缺陷细胞（步骤2）。在步骤3中，额外的体细胞突变发生在GPI缺陷型细胞中，导致进一步扩增并产生大量GPI锚缺陷型细胞（步骤3）。在这项研究中，我们报告了一个独特的PNH患者，其PIGA缺陷的造血细胞，而不是PIGA正常的细胞，有异常的两个染色体12，并确定了染色体断裂点在这个病人。此外，我们已经确定了一个强大的候选基因定位在这些断点之一。这可能与PNH克隆的克隆扩张有关。

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by the clonal expansion of glycosylphosphatidylinositol (GPI) deficient cells, leading to complement-mediated hemolysis. Several lines of evidence suggest that a somatic mutation of PIGA and additional abnormalities are necessary for the clonal expansion of the mutant clones. We propose the three-step model for the clonal expansion of the GPI deficient hematopoietic stem cells in PNH. Somatic mutation of PIG-A occurs in a hematopoietic stem cell, resulting in the deficiency of the surface expression of all GPI-anchored proteins (Step 1). Immunological attack on hematopoietic stem cells decreases the number of stem cells, positively selecting GPI-deficient cells (Step 2). In step 3, the additional somatic mutation occurs in a GPI-deficient ell, leading to further expansion and generation of a large number of GPI-anchor-deficient cells (Step 3). In this study, we reported a unique patient with PNH, whose PIGA-defective hematopoietic cells but not PIGA-normal cells, has abnormalities in both chromosomes 12 and determined the chromosomal breakpoints in this patient. Furthermore, we have identified a strong candidate gene localized at one of these breakpoints. It may be causally related to the clonal expansion of PNH clones.