Resistance to apoptosis caused by PIG-A gene mutations in paroxysmal nocturnal hemoglobinuria
Resistance to apoptosis caused by PIG-A gene mutations in paroxysmal nocturnal hemoglobinuria
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DOI：
10.1073/pnas.94.16.8756
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发表时间：
1997-08-05
影响因子：
11.1
通讯作者：
Jones, RJ
中科院分区：
文献类型：
--
作者：
Brodsky, RA;Vala, MS;Jones, RJ
阵发性夜间血红蛋白尿（PNH）是一种克隆性造血干细胞疾病，由x连锁基因piga突变引起，该基因编码糖基磷脂酰肌醇（GPI）锚定蛋白生物合成第一步所需的酶，piga突变导致所有GPI锚定蛋白的细胞表面表达缺失或减少。尽管该疾病的许多临床表现（如溶血性贫血）可以通过缺乏gpi锚定的补体调节蛋白（如CD59和CD55）来解释，但尚不清楚为什么PNH克隆主导造血功能，以及为什么它容易进化成急性白血病，研究者发现PIG-A突变通过使细胞相对抵抗凋亡性死亡而赋予生存优势。将PNH患者的粒细胞和受影响的CD34(+) （CD59(-)）细胞置于无血清培养基中，PNH患者的粒细胞和受影响的CD34(+) （CD59(-)）细胞存活时间比正常细胞长，PNH细胞对电离照射诱导的细胞凋亡也有相对的抗性，在PNH细胞系中替换正常的猪- a基因逆转了细胞对凋亡的抗性。猪- a突变导致的抑制细胞凋亡似乎是PNH细胞比正常祖细胞保持生长优势的主要机制，并可能在这种疾病转化为更具侵袭性的血液系统疾病的倾向中发挥作用。这些数据也表明GPI锚点在调节细胞凋亡中很重要。
Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disorder resulting from mutations in an X-linked gene, PIG-A, that encodes an enzyme required for the first step in the biosynthesis of glycosylphosphatidylinositol (GPI) anchors, PIG-A mutations result in absent or decreased cell surface expression of ali GPI-anchored proteins. Although many of the clinical manifestations (e.g., hemolytic anemia) of the disease can be explained by a deficiency of GPI-anchored complement regulatory proteins such as CD59 and CD55, it is unclear why the PNH clone dominates hematopoiesis and why it is prone to evolve into acute leukemia, me found that PIG-A mutations confer a survival advantage by making cells relatively resistant to apoptotic death. When placed in serum-free medium, granulocytes and affected CD34(+) (CD59(-)) cells from PNH patients survived longer than their normal counterparts, PNH cells were also relatively resistant to apoptosis induced by ionizing irradiation, Replacement of the normal PIG-A gene in PNH cell lines reversed the cellular resistance to apoptosis, Inhibited apoptosis resulting from PIG-A mutations appears to be the principle mechanism by which PNH cells maintain a growth advantage over normal progenitors and could play a role in the propensity of this disease to transform into more aggressive hematologic disorders. These data also suggest that GPI anchors are important in regulating apoptosis.