Neutral evolution in paroxysmal nocturnal hemoglobinuria
Neutral evolution in paroxysmal nocturnal hemoglobinuria
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DOI：
10.1073/pnas.0802749105
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发表时间：
2008-11-25
影响因子：
11.1
通讯作者：
Pacheco, Jorge M.
中科院分区：
文献类型：
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作者：
Dingli, David;Luzzatto, Lucio;Pacheco, Jorge M.
阵发性睡眠性血红蛋白尿症是一种获得性造血干细胞（HSC）疾病，其特征是糖基-磷脂酰肌醇（GPI）连接的膜蛋白部分或完全缺乏，导致血管内溶血。GPI生物合成所需的PIG-A基因的功能缺失突变解释了许多膜蛋白的缺乏如何由单个遗传事件引起。然而，迄今为止，GPI（-）克隆的扩增机制尚未完全理解。已经提出了两种假设：GPI（-）细胞由于二次突变而具有选择性优势，或者GPI（-）细胞在存在对正常（GPI（+））HSC的免疫攻击的情况下具有条件性生长优势。在这里，我们探索第三种可能性，即PNH克隆没有选择性优势。在一个大型虚拟群体中的模拟准确地再现了已知的疾病发病率;当干细胞数量减少时，拟合得到优化，反映了PNH中骨髓衰竭的一个组成部分。该模型还占自发治愈PNH的发生，随之而来的克隆灭绝。因此，克隆优势可能并不总是必要的解释PNH的克隆扩张。
Paroxysmal nocturnal hemoglobinuria is an acquired hematopoietic stem cell (HSC) disorder characterized by the partial or complete deficiency of glycosyl-phosphatidylinositol (GPI)-linked membrane proteins, which leads to intravascular hemolysis. A loss of function mutation in the PIG-A gene, required for GPI biosynthesis, explains how the deficiency of many membrane proteins can result from a single genetic event. However, to date the mechanism of expansion of the GPI(-) clone has not been fully understood. Two hypotheses have been proposed: A selective advantage of GPI(-) cells because of a second mutation or a conditional growth advantage of GPI(-) cells in the presence of an immune attack on normal (GPI(+)) HSCs. Here, we explore a third possibility, whereby the PNH clone does not have a selective advantage. Simulations in a large virtual population accurately reproduce the known incidence of the disease; and the fit is optimized when the number of stem cells is decreased, reflecting a component of bone marrow failure in PNH. The model also accounts for the occurrence of spontaneous cure in PNH, consequent on clonal extinction. Thus, a clonal advantage may not be always necessary to explain clonal expansion in PNH.