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

造血干细胞疾病中异常细胞克隆扩增的分子机制

• 批准号: 14370313
• 负责人: INOUE Norimitsu
• 金额: $ 8.32万
• 依托单位: Osaka Medical Center for Cancer and Cardiovascular Diseases
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370313/
• 关键词: Paroxysmal Nocturnal Hemoglobinuria; GPI anchor; Hematopoietic stem cell; HMGA2; Hemolytic anemia; Benign tumor; PIG-A; 造血幹細胞

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.

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，并确定在这个病人的染色体断裂点。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。

项目成果

Yeongjin Hong: "Human PIG-U and yeast Cdc91p are the fifth subunit of GPI transamidase that attaches GPI-anchors to proteins."Mol.Biol.Cell.. 14. 1780-1789 (2003)

Yeongjin Hong：“人 PIG-U 和酵母 Cdc91p 是 GPI 转酰胺酶的第五个亚基，可将 GPI 锚定物附着到蛋白质上。”Mol.Biol.Cell.. 14. 1780-1789 (2003)

Yashiko Murakami: "Inefficient response of T lymphocytes to Glycosylphosphatidylinositol-anchor-negative cells : implications for paroxysmal nocturnal hemoglobinuria"Blood. 100. 4116-4122 (2002)

Yashiko Murakami：“T 淋巴细胞对糖基磷脂酰肌醇锚定阴性细胞的低效反应：对阵发性睡眠性血红蛋白尿症的影响”血液。

Inoue, N., Kinoshita, T.: "GPI-GlcNAc Transferase (UDP-GlcNAc : Plα1-4GlcNAc transferase) : Complex of PIG-A, PIG-C, PIG-H, hGPI1 and PIG-P.(Handbook of Glycosyltransferases and Their Related Genes)(Eds. N.Taniguchi, K.Honke and M.Fukuda)"Springer-Verlag.

Inoue, N., Kinoshita, T.：“GPI-GlcNAc 转移酶（UDP-GlcNAc：Plα1-4GlcNAc 转移酶）：PIG-A、PIG-C、PIG-H、hGPI1 和 PIG-P 的复合物。（糖基转移酶手册） ）及其相关基因）（N.Taniguchi、K.Honke 和 M.Fukuda 编）“Springer-Verlag。

Taroh Kinoshita: "Relationship between aplastic anemia and paroxysmal nocturnal hemoglobinuria."Int.J.Hematology. 75. 117-122 (2002)

Taroh Kinoshita：“再生障碍性贫血和阵发性睡眠性血红蛋白尿之间的关系。”Int.J.Hematology。

Yeongjin Hong: "Requirement of N-glycan on GPI-anchored proteins for efficient binding aerolysin but not Clostridium septicum α-toxin."EMBO J.. 21. 5047-5056 (2002)

Yeongjin Hong：“GPI 锚定蛋白需要 N-聚糖才能有效结合气溶素，但不能结合败血梭菌 α-毒素。”EMBO J.. 21. 5047-5056 (2002)