Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH)
Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH)
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DOI：
10.1182/blood-2006-05-025148
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发表时间：
2006-12-15
期刊：
影响因子：
20.3
通讯作者：
Kinoshita, Taroh
中科院分区：
文献类型：
--
作者：
Inoue, Norimitsu;Izui-Sarumaru, Tomohisa;Kinoshita, Taroh
造血干细胞中PIGA的体细胞突变导致阵发性睡眠性血红蛋白尿症（PNH）中糖基磷脂酰肌醇锚定蛋白缺乏，这是血管内溶血的基础，但不能解释PNH克隆的扩增。免疫机制可能介导克隆选择，但似乎不足以解释PNH临床表现所需的克隆优势。在此，我们报告了2例PNH患者，其PIGA突变细胞同时发生了获得性12号染色体重排。在这两种情况下，der（12）在HMGA 2的3'非翻译区有一个断裂，HMGA 2是一种在许多良性间叶肿瘤中失调的结构转录因子基因，导致HMGA 2在骨髓中异位表达。这些观察结果表明，异常的HMGA2表达，与突变的PIGA，占克隆造血在这2例患者，并建议的概念PNH作为一种良性肿瘤的骨髓。
Somatic mutation of PIGA in hematopoietic stem cells causes deficiency of glycosyl phosphatidylinositol-anchored proteins in paroxysmal nocturnal hemoglobinuria (PNH) that underlies the intravascular hemolysis but does not account for expansion of the PNH clone. Immune mechanisms may mediate clonal selection but appear insufficient to account for the clonal dominance necessary for PNH to become clinically apparent. Herein, we report 2 patients with PNH whose PIGA-mutant cells had a concurrent, acquired rearrangement of chromosome 12. In both cases, der(12) had a break within the 3' untranslated region of HMGA2, the architectural transcription factor gene deregulated in many benign mesenchymal tumors, that caused ectopic expression of HMGA2 in the bone marrow. These observations suggest that aberrant HMGA2 expression, in concert with mutant PIGA, accounts for clonal hematopoiesis in these 2 patients and suggest the concept of PNH as a benign tumor of the bone marrow.