阵发性睡眠性血红蛋白尿症患者骨髓细胞生物学特征研究
摘要
【研究背景】
阵发性睡眠性血红蛋白尿症(PNH)是由体细胞X-染色体连锁,PIG-A基因突变导致的一种获得性血液学紊乱。最根本的特征是葡萄糖磷脂酰肌醇(GPI)锚定蛋白(GPI-APs)缺失或减少的造血干细胞克隆扩增，临床主要表现为溶血性贫血、血栓形成和造血功能障碍。
虽然发现PIG-A基因突变及其导致的一系列生化和分子机制异常已能较好地解释PNH部分临床表现，但还不足以说明PNH突变干细胞如何取代正常造血而获得在骨髓继而在外周血中的优势。目前，对于PNH细胞克隆主宰造血的机制有几种解释：1．与正常的造血干／祖细胞相比，缺乏GPI-APs的细胞可能存在内源性增殖优势进而使正常表型的细胞逐渐减少，这是解释体细胞PIG-A突变后发展为PNH的最简单的模型。但是，目前体外培养及对PIG-A基因敲除小鼠胚胎和小鼠嵌合体模型的研究结果不支持这种可能性。2．凋亡的减少也被提出为GPI阴性细胞持续存在及占据优势的原因。迄今为止对于突变的PNH细胞能否抵抗凋亡的研究结果尚不一致。3．环境因素施加的直接或间接的选择压力使PIG-A基因突变的细胞系得以扩增，即生存优势。另外，由于PNH与MDS和急性白血病的发生有关，有人假设PNH为白血病的多步发展过程中的一步，也有人假设AML与PNH更象是从某种相似因素影响下的背景各自发展而来的。Bessler认为还存在另一种过程能一过性的增加体细胞突变率(包括PIG-A基因突变)以减轻早期骨髓衰竭带来的选择压力。
PNH的常规治疗手段有：肾上腺皮质激素、雄激素、免疫抑制剂、抗凝治疗、以及红细胞输入等支持治疗。肾上腺皮质激素至今仍是治疗PNH的一种主要药物，但对激素无效或依赖的难治性／复发性PNH如何治疗，一直是棘手的难题。免疫抑制治疗对骨髓低增生PNH患者疗效较好，而对典型血红蛋白尿发作的PNH患者疗效欠佳。传统治疗有效的患者也易复发，而且治疗有效后，溶血指标并没有明显改善。造血干细胞移植术(SCT)是可能根治PNH的方法，但PNH是一个慢性的良性疾病，SCT10％～20％的相关死亡使其仅限于那些难治性、耐皮质激素或有激素禁忌症的患者。早在70年代末，苏联学者就报道环磷酰胺(CTX)或6-巯基嘌呤治疗PNH取得一定疗效。我们设计过几种化疗方案，也取得一定疗效，但仍不理想。国外还有使用G-CSF治疗PNH和刺激正常造血的报道。
OBJECTTIVES:
1 .To observe the efficacy and side effects of DA/HA chemotherapy on refractory
and relapsed paroxysmal nocturnal hemoglobinuria (PNH).
2.To compare the growth and the response of PNH and normal controls' bone
marrow mononuclear cells (BMMNCs) to the granulocyte colony-stimulating
factor (G-CSF) in vitro.
3.To study the expression of G-CSF receptor (G-CSFR)(CD114) and stem cell
factor (SCF) receptor (SCFR)(CD117) on BMMNCs of PNH patients and normal
controls.
4.To analyze normal and PNH patients' bone marrow (BM) neutrophils for
CD16b, apoptotic receptor Fas (CD95) and apoptosis related proteins Bcl-2 and
Bax.
METHOD:
1.Clinical trial:
8 patients with refractory and relapsed PNH were treated with DA/HA chemotherapy. The regimens were as following: 3 patients were treated with DA (DNR40 mg/d, i. v. drip, the first and the second day; 20mg/d, i. v. drip, the third day; Ara-C 100mg/d, i. v. drip, for 5 days), 5 patients were treated with HA (HHT 2mg/d~3mg/d, i.v.drip, for 5 days; Ara-C 100mg/d, i.v.drip, for 5 days). The therapeutic effects were observed.
2.In vitro culture:
BMMNCs from17 PNH patients and 12 normal controls were inoculated into semisolid culture, divided into two groups: one growed with G-CSF (50ng/ml), the other without. Then the cluster/colony forming unit-granulocyte/monocyte (CFU/cFU-GM) were observed and the effect of G-CSF were compared.
3.Mechanism investigation:
(1)BMMNCs of 20 PNH patients and 12 normal controls were triple stained for
阵发性睡眠性血红蛋白尿症(PNH)是由体细胞X-染色体连锁,PIG-A基因突变导致的一种获得性血液学紊乱。最根本的特征是葡萄糖磷脂酰肌醇(GPI)锚定蛋白(GPI-APs)缺失或减少的造血干细胞克隆扩增，临床主要表现为溶血性贫血、血栓形成和造血功能障碍。
虽然发现PIG-A基因突变及其导致的一系列生化和分子机制异常已能较好地解释PNH部分临床表现，但还不足以说明PNH突变干细胞如何取代正常造血而获得在骨髓继而在外周血中的优势。目前，对于PNH细胞克隆主宰造血的机制有几种解释：1．与正常的造血干／祖细胞相比，缺乏GPI-APs的细胞可能存在内源性增殖优势进而使正常表型的细胞逐渐减少，这是解释体细胞PIG-A突变后发展为PNH的最简单的模型。但是，目前体外培养及对PIG-A基因敲除小鼠胚胎和小鼠嵌合体模型的研究结果不支持这种可能性。2．凋亡的减少也被提出为GPI阴性细胞持续存在及占据优势的原因。迄今为止对于突变的PNH细胞能否抵抗凋亡的研究结果尚不一致。3．环境因素施加的直接或间接的选择压力使PIG-A基因突变的细胞系得以扩增，即生存优势。另外，由于PNH与MDS和急性白血病的发生有关，有人假设PNH为白血病的多步发展过程中的一步，也有人假设AML与PNH更象是从某种相似因素影响下的背景各自发展而来的。Bessler认为还存在另一种过程能一过性的增加体细胞突变率(包括PIG-A基因突变)以减轻早期骨髓衰竭带来的选择压力。
PNH的常规治疗手段有：肾上腺皮质激素、雄激素、免疫抑制剂、抗凝治疗、以及红细胞输入等支持治疗。肾上腺皮质激素至今仍是治疗PNH的一种主要药物，但对激素无效或依赖的难治性／复发性PNH如何治疗，一直是棘手的难题。免疫抑制治疗对骨髓低增生PNH患者疗效较好，而对典型血红蛋白尿发作的PNH患者疗效欠佳。传统治疗有效的患者也易复发，而且治疗有效后，溶血指标并没有明显改善。造血干细胞移植术(SCT)是可能根治PNH的方法，但PNH是一个慢性的良性疾病，SCT10％～20％的相关死亡使其仅限于那些难治性、耐皮质激素或有激素禁忌症的患者。早在70年代末，苏联学者就报道环磷酰胺(CTX)或6-巯基嘌呤治疗PNH取得一定疗效。我们设计过几种化疗方案，也取得一定疗效，但仍不理想。国外还有使用G-CSF治疗PNH和刺激正常造血的报道。
OBJECTTIVES:
1 .To observe the efficacy and side effects of DA/HA chemotherapy on refractory
and relapsed paroxysmal nocturnal hemoglobinuria (PNH).
2.To compare the growth and the response of PNH and normal controls' bone
marrow mononuclear cells (BMMNCs) to the granulocyte colony-stimulating
factor (G-CSF) in vitro.
3.To study the expression of G-CSF receptor (G-CSFR)(CD114) and stem cell
factor (SCF) receptor (SCFR)(CD117) on BMMNCs of PNH patients and normal
controls.
4.To analyze normal and PNH patients' bone marrow (BM) neutrophils for
CD16b, apoptotic receptor Fas (CD95) and apoptosis related proteins Bcl-2 and
Bax.
METHOD:
1.Clinical trial:
8 patients with refractory and relapsed PNH were treated with DA/HA chemotherapy. The regimens were as following: 3 patients were treated with DA (DNR40 mg/d, i. v. drip, the first and the second day; 20mg/d, i. v. drip, the third day; Ara-C 100mg/d, i. v. drip, for 5 days), 5 patients were treated with HA (HHT 2mg/d~3mg/d, i.v.drip, for 5 days; Ara-C 100mg/d, i.v.drip, for 5 days). The therapeutic effects were observed.
2.In vitro culture:
BMMNCs from17 PNH patients and 12 normal controls were inoculated into semisolid culture, divided into two groups: one growed with G-CSF (50ng/ml), the other without. Then the cluster/colony forming unit-granulocyte/monocyte (CFU/cFU-GM) were observed and the effect of G-CSF were compared.
3.Mechanism investigation:
(1)BMMNCs of 20 PNH patients and 12 normal controls were triple stained for
引文
1. Glycosyl-phosphatidylinositol (GPI)-anchored molecues and the pathogenesis of paroxysmal nocturnal hemoglobinuria. Hematology. 2000, 33:25-43.
2. Socie G, Mary JY, de Gramont A, et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet. 1996,348:573-7.
3. Hilmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995, 333:1253-8.
4. Ware RE, Hall SE, Rosse WF. Paroxysmal nocturnal haemoglobinuria with onset in childhood and adolescence. N Engl J Med. 1992, 325:991-996.
5. Rotoli B, Luzzatto L, Baillieres. Paroxysmal nocturnal haemoglobinuria. Clin Haematol. 1989,2:113-38.
6. Harris JW, Koscick R, Lazarus HM, et al. Leukemia arising out of paroxysmal nocturnal hemoglobinuria. Leuk Lymphoma. 1999,32:401-426.
7. Davitz MA, Low MG, Nussenzweig V. Release of decay-accelcrating factor (DAF) from the cell membrane by phosphatidylinositol-specific phospholipase C (PIPLC). Selective modification of a complement regulatory protein. J Exp Med. 1986, 163: 1150-61.
8. Bessler M, Hilmen P. Somatic mutation and clonal selection in the pathogenesis and in the control of paroxysmal nocturnal haemoglobinuria. 1998, 35(2): 149-67.
9. Rosse WF. Variations in the red cells in paroxysmal nocturnal haemoglobinuria. Br J Haematol. 1973,24:327-342.
10. Wendell F.Rosse New insights into paroxysmal nocturnal hemoglobinuria, Current Opinion in Hematology. 2001,8:61-67.
11.Maciejewski JP, Sloand EM, Sate T, et al. Impaired hematopoiesis in paroxysmal nocturnal hemoglobinurialaplastic anemia is not associated with a selective proliferative defect in the glycosylphosphatidylinositol-anchored protein-deficient clone. Blood, 1997, 89:1173-81.
12. Tseng JE, Hall SE, Howard TA, et al. Phenotypic and functional analysis of lymphocytes in paroxysmal nocturnal hemoglobinuria. Am J Hematol, 1995, 50: 244-53.
13. Rosti V, Tremml G, Soares V, et al. Embryonic stem cells without PIG-A gene activity are competent for hematopoieis with the PNH phenotype but notfor clonal expansion. J Clin Invest. 1997, 100:1028-1036.
14. Xiao J, Wu YJ, Zhang ZN, et al. Application of double immunomagnetic positive sorting to ex vivo expansion of marrow CD34(+) CD59(+) cells from patients with paroxysmal nocturnal hemoglobinuria. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2003, 11(2): 179-83.
15. Clark DA, Butler SA. Bessler M, et al. The kidneys in paroxysmal nocturnal hemoglobinuria. Blood. 1981,57:83-891. Karadimitris, Luzzatto L. The cellular pathogenesis of paroxysmal nocturnal hemoglobinuria. Leukemia, 2001, 15: 1148-1152.
2．邵宗鸿，赵明峰，李克，等 低剂量联合化疗对难治性、复发性阵发性睡眠性血红蛋白尿的疗效观察．中国实用内科杂志，2000，20：607-609．
3．张之南，沈悌，主编．血液病诊断及疗效标准．第2版．北京：北京科学出版社，1998．33-36．
4. Alfinito F, lo Pardo C, Boccuni P, et al. Reliable identification of the PNH defect on lymphocyte and monocyte membrane by CD48 MoAbs, In: Kishimoto T, Kikutani I-I, von dem Borne AEG, et al. eds. Leukocyte Typing Ⅵ. New York: Garland Publishing, 1997. 512-514.
5. Rosti V, Tremml G, Soares V, et al. Embryonic stem cells without PIG-A gene activity are competent for hematopoieis with the PNH phenotype but not for clonal expansion. J Clin Invest. 1997, 100: 1028-1036.
6. Taylor VC, Sims M, Brett S, et al. Antibody selection against CD52 produces a paroxysmal nocturnal haemoglobinuria phenotype in human lymphocytes by a novel mechanism. Biochem J. 1997, 322: 919-925.
7. Boccuni P, del Vecchio L, di Noto R, et al. Glycosyl-phosphatidylinositol (GPI)-anchored molecues and the pathogenesis of paroxysmal noctumal hemoglobinuria. Crit Rev Oncol Hematol. 2000, 33: 25-43.
8. Araten DJ, Nafa K, et al. Clonal populations of hematopoietic cells with paroxysmal noctumal hemoglobinuria genotype and phenotype are present in normal individuals. Proc. Natl. Acad. Sci. USA. 1999, 96(9): 5209-5214。1. Glycosyl-phosphatidylinositol(GPI)-anchored molecules and the pathogenesis of paroxysmal nocturnal hemoglobinuria. Hematology. 2000, 33: 25-43.
2. Fujioka S, Asai T. Prognostic features of paroxysmal nocturnal hemoglobinuria in Japan. Nippon Ketsueki Gakkai Zasshi. 1989, 52: 1386-94.
3. Zhang Z, Liu EK. Experiences in clinical diagnosis of paroxysmal noctumal hemoglobinuria. Chung Hua Nei Ko Tsa Chih. 1995, 34: 540-4.
4. Lu JC, Lin MT. Paroxysmal nocturnal hemoglobinuria: report of one case. Chung Hua Min Kuo Hsiao Erh Ko I Hsueh Hui Tsa Chih. 1989, 30: 323-5.
5. Le XF, Yang TY, Yang XY, Wang XM. Characteristics of paroxysmal nocturnal hemoglobinuria in China. Clinical analysis of 476 cases. Chin Med J. 1990, 103: 885-9.
6. Tseng JE, Hall SE, Howard TA, Ware RE. Phenotypic and functional analysis of lymphocytes in paroxysmal noctumal hemoglobinuria. Am J Hematol. 1995, 50: 244-53.
7. Tumen J, Kline LB, Fay JW, et al. Complement sensitivity of paroxysmal nocturnal hemoglobinuria bone marrow cells. Blood 1980, 55: 1040-6.
8. Maciejewski JP, Sloand EM, Sate T, et al. Impaired hematopoiesis in paroxysmal noctumal hemoglobinurialaplastic anemia is not associated with a selective proliferative defect in the glycosylphosphatidylinositol-anchored protein-deficient clone. Blood 1997, 89: 1173-81.
9. Nishimura J., Ware R. E., Bumette A., et al. The hematopoietic defect in PNH is not due to defective stroma but is due to defective progenitor cells. Blood Cells, Molecules & Diseases. 2002a, 29, 159-167.
10．肖娟，武永吉，张之南，等，阵发性睡眠性血红蛋白尿症患者骨髓CD34+CD59+细胞与CD34+CD59-细胞生物学性能的研究，中华血液学杂志，2003，第24卷，第4期，169-173．Chin J Hematol．April 2003，24，No．4，169-173．
11. Rosti V, Tremml G, Soares V, et al. Embryonic stem cells without PIG-A gene activity are competent for hematopoieis with the PNH phenotype but not for clonal expansion. J Clin Invest. 1997, 100: 1028-1036.
12. Kawagoe K, Kitarnura D, Okabe M, et al. Glycosylphos-phatidylinositol-anchor-deficient mice: implications for clonal??dominance of mutant cells in paroxysmal nocturnal hemoglobinuria. Blood 1996, 87:3600-6.
13.Tarutani M, itami S, Okabe M, et al. Issue-specific knockout of the mouse PIG-A gene reveals important roles for GPI-anchored: proteins in skin development. Proc Natl Acad Sci USA 1997,94:7400-5.
14.Tremml G, Dominguez C, Rostil V, et al: Increased sensitivity to complement and a decreased red cell life span in mice mosaic for a non-functional Piga gene. Blood. 1999, 94: 2945-54.
15.Murakami Y, Kinoshita T, Maeda Y, et al: Different roles of glycosylphosphatidylinositol in various hematopoietic cells as revealed by a mouse model of paroxysmal nocturnal hemoglobinuria [see comments]. Blood 1999,94:2963-2970.
16．孙卫民,王惠琴编著《细胞因子研究方法学》：p633—643
17.Schubert J, Scholz C, Geissler RG. G-CSF and cyclosporin induce an increase of normal cells in hypoplastic paroxysmal nocturnal hemoglobinuria. Ann Hematol. 1997 ,74(5):225-30.
18.Prince GM, Mguyen M, Lazarus HM., et al Brodsky RA, Terstappen LWMM, Medof E. Peripheral blood harvest of unaffected CD34+/CD38- hematopoietic precursors in paroxysmal nocturnal hemoglobinuria. Blood 1995; 86: 3381-3386.
19.Fujimi A, Matsunaga T, Kogawa K, et al, A patient with paroxysmal nocturnal haemoglobinuria in whom granulocyte colony-stimulating factor administration resulted in improvement of recurrent enterocolitis and its associated haemolytic attacks British Journal of Haematology, 2002, 119, 858-862.
20.Jego P, Le Strat A, Girard L, et al, Paroxysmal Nocturnal Hemoglobinuria: Efficacy of Prolonged Treatment With Granulocyte Colony-Stimulating Factor,Blood. 1997 Oct 1;90(7):2841-3.
21.Johnson RJ, Rawstron AC, Richards S, et al, Circulating Primitive Stem Cells in Paroxysmal Nocturnal Hemoglobinuria (PNH) Are Predominantly Normal in Phenotype But Granulocyte Colony-Stimulating Factor Treatment Mobilizes Mainly PNH Stem Cells. Blood, 91, No 12, 1998: 4504-4508.1．施均，骨髓增生异常综合征细胞周期异常及细胞周期调控基因表达谱的研究(博士学位论文)，p．54．
2. Shao Z, Zhang H, Chen G, et al. Expression and function of c-kit receptor in bone marrow mononuclear cells of patients with myelodysplastic syndromes. Chin Med J(Eng1). 2001, 114(5): 481-5.
3．孙卫民，王惠琴编著《细胞因子研究方法学》，p．633-669．
4. Michael K. Richards, Fulu Liu, Hiromi Iwasaki, et al., Pivotal role of granulocyte colony-stimulating factor in the development of progenitors in the common myeloid pathway. Blood. 2003, 102: 3562-3568.
5. JenniferA. L, Terrye E. P, William M. M, Evaluation of Cytokines for Expansion of the Megakaryocyteand Granulocyte Lineages, Stem Cells. 1997, 15: 198-206
6. K. Matsumura-Takeda, K. Kotosai, A. Ozakia, et al. Rat granulocyte colony-forming unit(CFU-G) assay for the assessment of drug-induced hematotoxicity. Toxicology in Vitro 16.2002, 281-288.
7. Small D, Levenstein M, Kim E, et al. STK-1, the human homologue of F1k-2/F1t-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci USA. 1994, 91: 459-63.
8. Rosnet O, Birnbaum D. Hematopoietic receptors of class Ⅲ receptor-type tyrosine kinases. Crit Rev Oncog. 1993, 4: 595-613.
9. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990, 6: 203-12.
10. Andre C, d'Auriol L, Lacombe C, et al. c-kit mRNA expression in human and murine hematopoietic cell lines. Oncogene. 1989, 4: 1047-9.
11. Hu ZB, Ma W, Uphoff CC, et al. c-kit expression in human megakaryoblastic leukemia cell lines. Blood. 1994, 83: 2133-44.
12. deCastro CM, Denning SM, Langdon S, et al. The c-kit proto-oncogene receptor is expressed on a subset of human CD3-CD4-CD8-(triple-negative) thymocytes. Exp Hematol. 1994, 22: 1025-33.
13. Gunji Y, Nakamura M, Osawa H, et al. Human primitive hematopoietic progenitor cells are more enriched in KIT low cells than in KIT high cells.??Blood. 1993, 82:3283-9.
14. Lammie A, Drobnjak M, Gerald W, et al. Expression of c-kit and kit ligand proteins in normal human tissues.J Histochem Cytochem. 1994, 42:1417-25.
15. Chui X, Egami H, Yamashita J, et al. Immunohistochemical expression of the c-kit proto-oncogene product in human malignant and non-malignant breast tissues. Br J Cancer. 1996, 73:1233-6.
16. Hibi K, Takahashi T, Sekido Y, et al. Coexpression of the stem cell factor and the c-kit genes in small-cell lung cancer. Oncogene. 1991, 6:2291-6.
17. Sekido Y, Takahashi T, Ueda R, et al. Recombinant human stem cell factor mediates chemotaxis of small-cell lung cancer cell lines aberrantly expressing the c-kit protooncogene. Cancer Res. 1993, 53:1709-14.
18. Krystal GW, Hines SJ, Organ CP. Autocrine growth of small cell lung cancer mediated by coexpression of c-kit and stem cell factor. Cancer Res. 1996, 56:370-6.
19. Hines SJ, Organ C, Kornstein MJ, et al. Coexpression of the ckit and stem cell factor genes in breast carcinomas. Cell Growth Differ. 1995, 6:769-79.
20. Ohashi A, Funasaka Y, Ueda M, et al. c-kit receptor expression in cutaneous malignant melanoma and benign melanotic naevi. Melanoma Res 1996, 6:25-30.
21. Turner A M, Zsebo KM, Martin F, et al. Nonhematopoietic tumor cell lines express stem cell factor and display c-kit receptors. Blood. 1992, 80:374-81.
22. Cascavill N, Pellegrino M, D' Arena G, et al. Cd117 (c-Kit) is a restricted antigen of acute myeloid leukemia and characterizes early differentiative levels of M5 FAB subtype. Hematologica. 1998, 83: 392-397.
23. Reilly JT. Receptor tyrosine kinases in normal and malignant haematopoiesis. Blood Rev. 2003 Dec, 17:241-8.
24. Mol CD, Lim KB, Sridhar V, et al. Structure of a c-kit product complex reveals the basis for kinase transactivation. J. Biol. Chem. 2003, 278: 31461-31464.
25. Ashman LK, Cambareri AC, To LB, et al. Expression of the YB5.B8 antigen (c-kit proto-oncogene product) in normal human bone marrow. Blood. 1991, 78:30-7.
26. BENE MC, BERNIER M, CASASNOVAS RO, et al. The European Group for the Immunological Classi?cation of Leukemias (EGIL). The reliabilityand speci?city of c-kit for the diagnosis of acute myeloid leukemias and undifferentiated leukemias. Blood 1998,92:596-599.
27. BUE HRING HJ, ULLRICH A, SCHAUDT K, et al. The product of the proto-oncogene c-kit (P145c-kit) is a human bone marrow surface antigen of hemopoietic precursor cells which is expressed on a subset of acute non-lymphoblastic leukemic cells. Leukemia 1991,5: 854-860.
28. REUSS-BORST MA, BUE HRING HJ, SCHMIDT H, MUE LLER CA. AML: immunophenotypic heterogeneity and prognostic signi?cance of c-kit expression. Leukemia 1994,8:258-263.
29. Morita S, Tsuchiya S, Fujie H, et al. Cell surface c-kit receptors in human leukemia cell lines and pediatric leukemia: selective preservation of c-kit expression on megakaryoblastic cell lines during adaptation to in vitro culture. Leukemia 1996, 10:102-5.
30. Ashman LK, Buhring HJ, Aylett GW, et al. Epitope mapping and functional studies with three monoclonal antibodies to the c-kit receptor tyrosine kinase, YB5.B8, 17F11, and SR-1. J Cell Physiol 1994, 158:545-54.
31. Siitonen T, Savolainen ER, Koistinen P. Expression of the c-kit protooncogene in myeloproliferative disorders and myelodysplastic syndromes. Leukemia 1994, 8:631-7.
32. Muroi K, Nakamura M, Amemiya Y, et al. Expression of c-kit receptor (CD117) and CD34 in leukemic cells. Leuk Lymphoma 1995, 16:297-305.
33. Sincock PM, Ashman LK. Expression of c-Kit and functional drug efflux are correlated in de novo acute myeloid leukemia. Leukemia 1997, 11: 1850-1857.
34. Bendall LJ, Makrynikola V, Hutchinson A, et al. Stem cell factor enhances the adhesion of AML cells to fibronectin and augments fibronectin-mediated anti-apoptotic and proliferative signals. Leukemia 1998, 12: 1375-1382.
35. Scolnic MP, Morilla R, de Bracco MM, et al. CD34 and CD117 are overexpression in AML may be valuable to detect minimal residual disease. Leuk Res 2002, 26: 615-619.
36. Wozniak J, Kopec-Szlezak J. C-Kit receptor (CD 117) expression on myeloblasts and white blood cell counts in acute myeloid leukemia. Cytometry. 2004, Mar, 58B(1): 9-16.
37. Rotoli B, Luzzatto L. Paroxysmal nocturnal haemoglobinuria. Baillieres. Clin??Haematol. 1989,2:113-38.
38. Harris JW, Koscick R, Lazarus HM, et al. Leukemia arising out of paroxysmal nocturnal hemoglobinuria. Leuk Lymphoma. 1999,32:401-426.1. Malech H. L, J I Gallin. Neutrophils in human diseases. N Engl J Med. 1987,317:687.
2. Weiss, S. J. Tissue destruction by neutrophils. N Engl J Med. 1989, 320:365.
3. Savill J S, A H Wyllie, J E Henson, et al. Macrophage phagocytosis of aging neutrophils in inflammation-programmed cell death in the neu-trophil leads to its recognition by the macrophages. J. Clin. In-vest. 1989, 83:865.
4. Meagher L C, J S Savill, A Baker, et al. Phagocytosis of apoptotic neutrophils does not induce macro- phage release of thromboxane. Leukocyte Biol. 1992,52:269.
5. Whyte M. B., L. C. Meagher, J. MacDermot, et al. Impairment of function in aging neutrophils is associated with ap- optosis. J. Immunol. 1993,150:5124.
6. Ravetch JV, Perussia B. Alternative membrane forms of Fc RIII (CD 16) on human natural killer cells and neutrophils. J Exp Med. 1989,170:481-497.
7. Crockett T E, Smith CW, Kateley JR. et al. Insoluble immune complex-stimulated neutrophil leukotriene B4 production is dependent on FcyRII and FcyRIII and independent of pertussis toxin-sensitive signal transduction pathways. Am J Pathol. 1992, 140:613.
8. Hundt M, Schmidt RE. The glycosylphosphatidylinositollinked Fcγ receptor III represents the dominant receptor structure for immune complex activation of neutrophils. Hannover, Germany, Hannover Medical School. Eur J Immunol. 1992,22:811.
9. Brunkhorst B. A., G. Strohmeier, K. Lazzarin, et al. Differential roles of Fc Y R II and Fc Y R III in immune complex stimulation of human neutrophils. J. Biol. Chem. 1992, 29:20659.,
10. Zhou M. J., R. F. Todd, J. G. J. van de Winkel, et al. Cocapping of the leukoadhesin molecules complement receptor type 3 and lymphocyte function-associated antigen-1 with Fc-receptor III on human neutrophils. J. Immunol. 1993, 150:3030.
11. Schubert J, Vogt HG, Zielinska-Skowronek M, et al. Development of the glycosylphosphatitylinositol-anchoring defect characteristic for paroxysmal nocturnal hemoglobinuria in patients with- aplastic anemia. Blood. 1994,83:2323-8.
12. Hundt M, Jorg Schubert, Masja de Haas, et al. The Loss of FcyRIIIb in??Paroxysmal Nocturnal Hemoglobinuria Is Functionally Replaced by FcyRII. Blood. 1994,Vol83,No 12,3574-3580.
13. Ian Dransfield, Anne-Marie Buckle, et al. Neutrophil Apoptosis Is Associated with a Reduction in CD 16 (FcyRIII) Expression. The Journal of Immunology, 1994, 153: 1254.
14. Brach MA, de Vos S, Gruss HJ, et al. Prolongation of survival of human polymorphonuclear neutrophils by granulocytemacrophage colony-stimulating factor is caused by inhibition of programmed death. Blood. 1992, 80:2920.
15. Chitinis D, Dickerson C, Munster AM, et al. Inhibition of apoptosis in polymorphonuclear neutrophils from burn patients. J Leukoc Bio. 1996, 59:835.
16. Christa H E, Masja de Haas, Albert E.G.Kr, et al. Human Neutrophils Lose Their Surface FcyRIII and Acquire Annexin V Binding Sites During Apoptosis In Vitro. Blood. 1995, 85, 532-540.
17. Boros P., Odin J. A., Chen J., et al. Specificity and class distribution of FcgR-specific autoantibodies in patients with autoimmune disease. J. Immunol. 1994, 152,302-306.
18. Lamour A., Le Corre R., Pennec Y. L., et al. Heterogeneity of neutrophil antibodies in patients with primary Sjo|¨gren's syndrome. Blood .1995,86, 3553-3559.
19. Lamour A., Baron D., Soubrane C, et al. Anti-Fc gamma receptor III autoantibody is associated with soluble receptor in rheumatoid arthritis serum and synovial fluid. J. Autoimmun. 1995,8: 249-265.
20. Veronique Durand, Yves Renaudineau, Jacques-Olivier Pers, et al. Human FcγRIIIb Induces the Production of Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor by Polymorphonuclear Neutrophils. J Immunol. 2001, 167(7): 3996-4007.
21.Weinmann P., P. Gaehtgens B. Walzog. Bcl-x_L and Bax-α-mediated regulation of human neutrophils via caspase-3. Blood. 1999,93:3106.
22. Liles WC, Klebanoff SJ. Regulation of apoptosis in neutrophils-Fas track to death? J Immunol. 1995,155(7): 3289-91.
23. Issaragrisil S, U-pratya Y, Yimyam M, et al. Hematopoitic progenetor cells in the blood and marrow in various hematologic disorders. Stem Cells. 1998,16:123-128.24. Chen G., Kirby M., Zeng W., et al. Superior growth of glycophosphatidylinositol-anchored protein-deficient progenitor cells in vitro is due to the higher apoptotic rate of progenitors with normal phenotype in vivo. Experimental Hematology. 2002, 30: 774-782.
25. Brodsky R.A., Vala M.S., Barber J.P., et al. Resistance to apoptosis caused by PIG-A gene mutations in paroxysmal nocturnal hemoglobinuria. Proceedings of the National Academy of Sciences. 1997, 94:8756-8760.
26. Bessler M. Paroxysmal nocturnal hemoglobinuria: insights from resent advances in molecular biology. Transfusion Medicine Reviews.2001, Vol 15,255-267.
27. Ware RE, Nishimura J, Moody MA, et al. The PIG-A mutation and absence of glycosylphosphatidylinositol-linked proteins do not confer resistance to apoptosis in paroxysmal nocturnal hemoglobinuria. Blood. 1998,2541-2550.
28. Horikawa K, Nakakuma H, Kawaguchi T, et al. Apoptosis resistance of blood cells from patients with paroxysmal nocturnal hemoglobinuria, aplastic anemia, and myelodysplastic syndrome. Blood 1997,90:2716-22.
29. J. C. W. Marsh, M. O. Elebute, Stem cells in paroxysmal nocturnal haemoglobinuria and aplastic anaemia: increasing evidence for overlap of haemopoietic defect. Transfusion Medicine. 2003, 13(6), 377.
1. Glycosyl-phosphatidylinositol(GPI)-anchored molecues and the pathogenesis of paroxysmal nocturnal hemoglobinuria. Hematology. 2000, 33:25-43.
2. Strubing P. Paroxysmale Hlmoglobinurie. Dtsch Med Wochenschr 1882;8:1.
3. Karadimitris, Luzzatto L, The cellular pathogenesis of paroxysmal nocturnal hemoglobinuria. Leukemia. 2001, 15: 1148-1152.
4. Socie G, Mary JY, de Gramont A, et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet. 1996,348:573-7.
5. Hilmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995, 333:1253-8.
6. Ware RE, Hall SE, Rosse WF: Paroxysmal nocturnal haemoglobinuria with onset in childhood and adolescence. N Engl J Med. 1992, 325:991-996.
7. Rotoli B, Luzzatto L. Paroxysmal nocturnal haemoglobinuria.Baillieres. Clin Haematol. 1989,2:113-38.
8. Harris JW, Koscick R, Lazarus HM, et al. Leukemia arising out of paroxysmal nocturnal hemoglobinuria. Leuk Lymphoma. 1999,32:401-426.
9. Cowall DE, Pasquale DN, Dekker P. Paroxysmal nocturnal hemoglobinuria terminating as erythroleukemia. Cancer. 1979,43:1914-6.
10. Carmel R, Coltman CA, Yatteau RF, Costanzi JJ. Association of paroxysmal nocturnal hemoglobinuria with erythroleukemia. N Engl J Med. 1970,283:1329-31.
11. Zittoun R, Bernadou A, James JM, Soria J, Bousser J. Acute myelo-monocytic leukaemia: a terminal complication of paroxysmal nocturnal haemolobinuria. Acta Haematol. 1975,53:241-8.
12. Graham DL, Gastineau DA, Paroxysmal nocturnal hemoglobinuria as a marker for clonal myelopathy. Am J Med. 1992,93:671 -4.
13. Meri S, Morgan BP, Davies A, et al. Human protectin (CD59), an 18 000-20 000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers. Immunofogy 1990;71: 1-9.
14. Wendell F., Rosse ,Russell E.Ware, The molecular basis of paroxysmal nocturnal hemoglobinuria. Blood, 1995, 86:3277-3286.
15. Zupanska B, Uhrynowska M, Konopka L. Transfusion-related acute lung injury due to granulocyte-agglutinating antibody in a patient with paroxysmal nocturnal hemoglubinuria.Transfution. 1999,39:944-977.
16. Clark DA, Butler SA. Bessler M, et al. The kidneys in paroxysmal nocturnal hemoglobinuria. Blood. 1981,57:83-89.
17. Hartmann RC, Bruce ASC. Fetomaternal outcomes of pregnancy in paroxysmal nocturnal hemoglobinuria. In Hematologic Disorders in Maternal-Feternal Medicine. New York, Wiley-Liss; 1993:261 -281.
18. Wiedmer T, Hall SE. , Ortel TL. Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria and aplastic anemia.Blood 1993,82:1192-1196.
19. Hugel B, Socie G, Vu T,et al. elevated levels of circulating procogulant microparticles in parients with paroxysmal nocturnal hemoglobinuria and aplastic anemia.Blood1999,93:3451-3464.
20. Hamilton KK, Hattori R, Esmon CT, Sims PJ. Complement proteins C5b-9 induce vesiculation of the endothelial plasma membrane and expose catalytic surface for assembly of the prothrombinase enzyme complex. J Biol Chem 1990;265:3809-14.
21. Wendell F.Rosse New insights into paroxysmal nocturnal hemoglobinuria, Current Opinion in Hematology 2001,8:61-67.
22. Ploug M, Plesner T, Ronne E, Ellis V, Hoyer-Hansen G,Hansen NE, et al. The receptor for urokinase-type plasminogen activator is deficient on peripheral blood leukocytes in patientswith paroxysmal nocturnal hemoglobinuria.Blood. 1992, 79: 1447-55.
23. Moiler LB. Structure and function of the urokinase receptor.Blood Coagul Fibrinol 1993;4:293-303.
24. Liebman HA. , Feinstein DI. , Thrombosis in patients with paroxysmal noctural hemoglobinuria is associated with markedly elevated plasma levels of leukocyte-derived tissue factor. Thromb Res. 2003, 111(4-5):235-8.
25. Hall C, Richards S, Hillmen P., Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2003, 102:3587-91.
26. Fujioka S, Asai T. Prognostic features of paroxysmal nocturnal hemoglobinuria in Japan. Nippon Ketsueki Gakkai Zasshi. 1989,52: 1386-94.
27. Zhang Z, Liu EK. Experiences in clinical diagnosis of paroxysmal nocturnal hemoglobinuria. Chung Hua Nei Ko Tsa Chih.1995, 34:540-4.
28. Lu JC, Lin MT. Paroxysmal nocturnal hemoglobinuria: report of one case. Chung Hua Min Kuo Hsiao Erh Ko I Hsueh Hui Tsa Chih. 1989,30:323-5.
29. Le XF, Yang TY, Yang XY, Wang XM. Characteristics of paroxysmal nocturnal hemoglobinuria in China. Clinical anaiysis of 476 cases. Chin Med J. 1990,103:885-9.
30. Davitz MA, Low MG, Nussenzweig V. Release of decay-accelcrating factor (DAF) from the cell membrane by phosphatidylinositol-specific phospholipase C (PIPLC). Selective modification of a complement regulatory protein. J Exp Med 1986,163: 1150-61.
31. Ham TH, Dingle JH. Studies on the destruction of red blood cells. II. Chronic hemolytic anemia with paroxysmal nocturnal hemoglobinuria: certain immunological aspects of the hemolytic mechanism with special reference to serum complement. J Clin Invest 1938,18:657-72.
32. Hartmann RC, Jenkins DJE: The "suger water" test for paroxysmal nocturnal hemoglobinuria. New Engl J Med. 1996,275:155-155.
33. Rosse WF, Dacie JV: Immune lysis of paroxysmal nocturnal hemoglobin red blood cells.I.The sensitivity of PNH red cells to lysis by complement and specific antibody. J Clin Invest 1966,45:736-748.
34. Hall S, Rosse WF: The use of monoclonal antibody and flow cytometry in the diagnosis of paroxysmal nocturnal hemoglobinuria. Blood 1996, 87:5332-5340.
35. Richard SJ, Rawstron AC, Hilmen P: Application of flow cytometry in the diagnosis of paroxysmal nocturnal hemoglobinuria. Cytometry.2000,42:223-233.
36. Van der Schoot CE, Huizinga TW, van't Veer-Korthof ET, W1 Jmans R, Pinkster J, von dem Borne AE. Deficiency of glycosyl-phosphatidylinositol-linked membrane glycoproteins of leukocytes in paroxysmal nocturnal hemoglobinuria, description of a new diagnostic cytofluorometric assay . Blood 1990, 76: 1 853 -9.37. Plesner T, Hansen NE, Carlsen K. Estimation of Pi-bound proteins on blood cells from PNH patients by quantitative flow cytometry. Br J Haematol 1990,75:585-90.
38. Schubert J, Vogt HG, Zielinska-Skowronek M, Freund M. Kaltwasser JP, Hoelzer D, et al. Development of the glycosylphosphatitylinositol-anchoring defect characteristic for paroxysmal nocturnal hemoglobinuria in patients with- aplastic anemia. Blood 1994,83:2323-8.
39. Nakakuma H, et al. Paroxysmal nocturnal hemoglobinuria clone in bone marrow of patients with pancytopenia. Blood 1995,85: 1371-6.
40. Alfinito F, Lo Pardo C, Boccuni P, Pandolfi G, Del Vecchio L and Rotoli B. Reliable identification of the PNH defect on lymphocyte and monocyte membrane by CD48 MoAbs, In: Kishimoto T, Kikutani I-I, von dem Borne AEG et al., editors. Leukocyte Typing VI. New York: Garland Publishing, 1997,. 512-514.
41. Krauss JS. Laboratory diagnosis of paroxysmal nocturnal hemoglobinuria. Ann Clin Lab Sci, 2003, 33: 401-6.
42. Bessler M, Hilmen P. Somatic mutation and clonal selection in the pathogenesis and in the control of paroxysmal nocturnal haemoglobinuria. 1998, 35(2):149-67.
43. Rosse WF. Variations in the red cells in paroxysmal nocturnal haemoglobinuria. Br J Haematol 24:327-342, 1973
44. Kinoshita T, Ohishi K, Takeda J. GPI-Anchor synthesis in mammalian cells gene, their products,and a deficiency.J. Biochem. 1997, 122,251-157.
45. Ferguson Mkl. Glycosyl-phosphatidylinositol membrane anchor: The tale of a tail. Biochem Soc Transactions 1992 ,20:243-256.
46. Takahashi M, Inoue N, Ohishi K, et al: PIG-B, a membrane protein of the endoplasmic reticulum with a large lurnenal domain, is involved in transfering the thrid mannose of tire GPI-anchor. EMBO J 1996,15:4254-4261.
47. Vidugiriene J, Menon AK. The GPI-anchor of cell surface proteins is synthesized on the cytoplasmatic face of the endoplasmatic reticulum. J Cell Biol 1994,127:333-341.
48. Petty HR, Todd RF. Integrins as promiscuous signal transduction devices. 1996,17:209-212.
49. Casey PJ. Protein lipidation in cell signaling. Science 1995,268:221-5.
50. Robinson PJ. Phosphatidylinositol membrane anchors and T-cell activation. Immunol Today, 1991,12:35-41
51. Stefanova I, Horsejsi V, Ansotegui U, et al. GPI anchored cell surface molecules complexed to protein tyrosine kinases Sciencel991, 254:1016-1019,
52. Brown D, Ross J. Sorting of GPI-linked; proteins to glycolipid enriched membrane subdomains during transport to the apical cell surface. Cell, 1992, 68:533-544.
53. Sargiacomo M, Sudol M, Tang Z, et al. Signal transducing molecules and glycolyl phosphatidylinositol linked proteins form a caveolin rich insoluble complex in MDCK cells. J Cell Biol 1993, 122:789-807.
54. Harder T, Simons K, Caveolae. DIGS, and the dynamics of sphingolipid-cholesteroi microdomains. Curr Opin Cell Biol, 1997, 9:534-42.
55. Anderson RGW, Kamen BA, Rotenberg KG, et al. Protocytosis: sequestration and transport of small molecules by caveolae. Science, 1992, 255:410-411.
56. Brett SJ, Baxter G, Cooper H, et al. Emergence of CD52-,glycosylphosphatidylinositol-anchor-deficient lymphocytes in rheumatoid arthritis patients following Campath-IH treatment. Int Immunol, 1996, 8:325-334.
57. Daniels G: Cromer related antigens-blood group determinants on decay acceleration factor. Vox Sang, 1989, 56:205-211.
58. Davitz MA, Hereld D, Shak S, et al: A glycanphosphatidylinositol-specific phosphoiipase D in human serum. Science, 1987, 238:81-84.
59. Cross AGM: Cellular and genetic aspects of antigenic variation in trypanosomes. Ann Rev Immunol 8:83-110, 1990 19.
60. Ueda E, Sevlever D, Prince GM, Rosenberry TL, et al. A candidate mammalian glycoinositol phospholipid precursor containing three phosphoethanolamines. J Biol Chem, 1993,268:9998-10002.
61. Ueda E, Nishimura J-I, Kitani T, et al. Deficient surface expression of glycosylphosphatidylinositol-anchored proteins in B cell lines established from patients with paroxysmal nocturnal hemoglobinuria. Int Immunol 1992;4:1263-71.
62. Hillmen P, Bessler M, Crawford DH, Luzzatto L. Production and characterization of lymphoblastoid cell lines with the paroxysmal nocturnal hemoglobinuria phenotype. Blood 1993,81:193-9.
63. Sugiyama E, DeGasperi R, Urakaze M, et al. Identification of defects in glycosylphosphatidylinositol anchor biosynthesis in the Thy-1 ex pression mutants. J Biol Chem. 1991, 266:12119-22.
64. Armstrong C, Schubert J, Ueda E, Knez JJ, Gelperin D, Hirose S, Silber R, Hollan S, Schmidt RE, Medof ME: Affected paroxysmal nocturnal hemoglobinuria T lymphocytes harbor a common defect in assembly of N-acetyl-D-gl ucosamine inositol phospholipid corresponding to that in class A Thy-1-murine lymphoma mutants. J Biol Chem 1992,267:25347.
65. Norris J, Hall S, Ware RE, Kamitani T,et al. Glycosyl-phosphatidylinositol anchor synthesis in paroxysmal nocturnal hemoglobinuria: Partial or complete defect in an early step. Blood 1994,83:816.
66. Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T, Takahashi M. Kitani T, Kinoshita T: Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell 73:703. 1993
67. Bessler M, Mason PJ, f-Iillmen P, et al. Paroxysmal nocturnal hemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. EMBO J 1994,13. 110.
68. Bessler M, Hillmen P, Longo L, et al. Genomic organization of the X-linked gene (PIG-A) that is mutated in paroxysmal nocturnal haemoglobinuria and of a related autosomal pseudogene mapped to 12q21. Hum Melee Genetl994, 3:751.
69. Bessler M. Paroxysmal nocturnal hemoglobinuria: insights from resent advances in molecular biology. Transfusion Medicine Reviews.2001, Vol 15,255-267.
70. Rollinson S, Richards S, Norfolk D, et al. Both paroxysmal nocturnal hemoglobinuria (PNH)type II cells and PNH type III cells can arise from different point mutations involving the same codon of the PIG-A gene. Blood 1997,89:3069-71.
71. Bessler M, Mason PJ, Hillmen Pet al. Somatic mutations and cellular selection inparoxysmal nocturnal haemoglobinuria. Lancet.343: 951-953.
72. Nafa K, Mason PJ, Hillmen P, et al. Mutations in the PIG-A gene causing paroxysmal??nocturnal hemoglobinuria are mainly of the frameshift type. Blood. 1995, 86:4650-5.
73. Kawagoe K, Takeda J, Endo Y, et al. Molecular cloning of murine PIG-A, a gene for GPI-anchor biosynthesis, and demonstration of interspecies conservation of its structure, function, and genetic locus. Genomics 1994,23:566-74.
74. Iida Y, Takeda J, Miyata T, et al. Characterization of genomic PIG-A gene: a gene for glycosylphosphatidylinositol-anchor biosynthesis and paroxysmal nocturnal hemoglobinuria. Blood 1994,83:3126-31.
75. Yamada N, Miyata T, Maeda K, Kitani T, Takeda J, Kinoshita T. Somatic mutations of the PIG-A gene found in Japanese patients with paroxysmal nocturnal hemoglobinuria. Blood 1995,85:885-92.
76. Nishimura J, fnoue N; Wada H, et al. A patient with paroxysmal nocturnal hemoglobinuria bearing four independent PIG-A mutant clones, Blood 1997,89:3470-6.
77. Endo M, Ware RE, Vreeke TM, et al. A patient with paroxysmal nocturnal hemoglobinuria (PNH) with an inherited mutation in PIG-A. Blood 1994,84:555a, (abstr, suppl 1).
78. Maciejewski JP, Sloand EM, Sate T, et al. Impaired hematopoiesis in paroxysmal nocturnal hemoglobinurialaplastic anemia is not associated with a selective proliferative defect in the glycosylphosphatidylinositol-anchored protein-deficient clone. Blood, 1997, 89:1173-81.
79. Tseng JE, Hall SE, Howard TA, Ware RE. Phenotypic and functional analysis of lymphocytes in paroxysmal nocturnal hemoglobinuria. Am J Hematol, 1995, 50:244-53
80. Rosti V,Tremml G, Soares V, et al. Embryonic stem cells without PIG-A gene activity are competent for hematopoieis with the PNH phenotype but not for clonal expansion. J Clin Invest. 1997, 100:1028-1036.
81. Xiao J, Wu YJ, Zhang ZN, et al. Application of double immunomagnetic positive sorting to ex vivo expansion of marrow CD34(+)CD59(+) cells from patients with paroxysmal nocturnal hemoglobinuria. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2003 ,11(2): 179-83.
82. Kawagoe K, Kitamura D, Okabe M, et al. Glycosylphos-phatidylinositol-anchor-deficient mice: implications for clonal dominance of mutant cells in paroxysmal nocturnal hemoglobinuria. Blood 1996, 87:3600-6.
83. Tarutani M, itami S, Okabe M, et al. Issue-specific knockout of the mouse PIG-A gene reveals important roles for GPI-anchored: proteins in skin development. Proc Natl Acad Sci USA 1997,94:7400-5.
84. Tremml G, Dominguez C, Rostil V, et al: Increased sensitivity to complement and a decreased red cell life span in mice mosaic for a non-functional Piga gene. Blood. 1999, 94: 2945-54.
85. Murakami Y, Kinoshita T, Maeda Y, et al: Different roles of glycosylphosphatidylinositol in various hematopoietic cells as revealed by a mouse model of paroxysmal nocturnal hemoglobinuria [see comments]. Blood 1999,94:2963-2970.
86. Wood SA, Alien ND, Rossant J, et al. Noninjection methods for the production of embryonic stem cellembryo chimaeras. Nature 1993,365:87-90.
87. Keller P.Tremml G,Rosti V, et al. X inactivation and somatic cell selection rescue female mice carrying a Piga-null mutation .Pro Natl Acad Sci U S A 1999,96:7479-7483.88. Iwamoto,N.,et al.l996.Preferential hematopoiesis by paroxysmal nocturnal hemoglubinuria clone engrafted in SCID mice.Blood.87:4944-4948.
89. Sammar M, Aigner S, Hubbe M, Schirrmacher V, Schachner M, Vestweber D, et al. Heat-stable antigen (CD24) as ligand for mouse P-selectin. Int Immunol 1994,6:1027-36.
90. Craig W, Kay R, Cutler RL, et al. Expression of Thy-1 on human hematopoietic progenitor cells. J Exp Med 1993,177:1331-42.
91. Brodsky RA.Vala MS,Barber JP,et al.: Resistance to apoptosis caused by PIG-A gene mutations in paroxysmal nocturnal hemoglobinuria.Proc Natl Acad Sci(USA) 1997,94:8756-8760.
92. Ware RE, Nishimura J, Moody MA, et al. The PIG-A mutation and absence of glycosylphosphatidylinositol-linked proteins do not confer resistance to apoptosis in paroxysmal nocturnal hemoglobinuria. Blood 1998,2541-2550.
93. Issaragrisil S, U-pratya Y, Yimyam M, et al. Hematopoitic progenetor cells in the blood and marrow in various hematologic disorders.Stem Cells 1998,16:123-128.
94. Horikawa K, Nakakuma H, Kawaguchi T, ct al. Apoptosis resistance of blood cells from patients with paroxysmal nocturnal hemoglobinuria, aplastic anemia, and myelodysplastic syndrome. Blood 1997,90:2716-22.
95. Araten DJ, Luzzatto L, Notaro R. Severe telomere shortening in patients with paroxysmal nocturnal hemoglobinuria affects both GPI- and GPI+ hematopoiesis. Blood, 2003, 102(2): 514-6.
96. Dacie JV, Gilpin A: Refractory anaemia (Fanconi type). Arch Dis Child. 1944, 19:155-162,
97. Tumen J, Kline LB, Fay JW, et al. Complement sensitivity of paroxysmal nocturnal hemoglobinuria bone marrow cells. Blood 1980,55:1040-6.
98. Rotoli B, Robledo R, Luzzatto L. Decreased number of circulating BFU-Es in paroxysmal nocturnal hemoglobinuria. Blood 1982,60: 157-9.
99. Nissen C, Tichelli A, et al.: High incidence of transiently appearing complement-sensitive bone marrow precursor cells in patients with severe aplastic anemia-A possible role of high endogenous IL-2 in their suppression. Acta Haematol. 1999,101:165-172.
100. Schrezenmeier H, Hertenstein B, Wagner B, et al. A pathogenetic link between aplastic anemia and paroxysmal nocturnal hemoglobinuria is suggested by a high frequency of aplastic anemia patients with a deficiency of phosphatidylinositol glycan anchored proteins. Exp Hematol 1995;23:81-7.
101. Daniel E.Dunn, Patcharin Tanawattanacharoen, et al. Paroxysmal nocturnal hemoglubinuria cells in patients with bone marrow failure syndromes. Ann Intern Med. 1999,131(6):401-8.
102. Bacigalupo A, Hows J, Gluckrnan E, et al. Bone marrow transplantation (BMT) versus immunosupression for the treatment of severe aplastic anemia (SAA): A report of the EBMT SSA Working Party. Br J Haematol. 1988, 70: 177-182.
103. Balleari E, Gatti AM, Mareni C, et al. Recombinant human erythropoietin for long-term treatment of anemia in paroxysmal nocturnal hemoglobinuria. Haematologica 1996,81:143-147.
104. Mathe G, Amiel J, Schwarzenberg L, et al: Bone marrow graft in man after condidtioningby antilymphocyte globuline. Br Med J 1970,2:131-136.
105. Socie G, Henry-Amar M,et al. Malignant tumors occurring after treatment of aplastic anemia .European Bone Marrow Transplantation—Severe Asplatic Anemia Working Party.N Engl J Med. 1993,329:1153-7.
106. Yong NS. The problem of clonality in aplastic anemia: Dr Dameshek's riddle,restated .Blood. 1992,79:1385-92.
107. Ware RE, Howard TA, Kamitani T, Chang H-M, Yeh TH, Seldin MF. Chromosomal assignment of genes involved in glycosylphosphatidylinositol anchor biosynthesis: implications for the pathogenesis of paroxysmal nocturnal hemogtobinuria.Blood 1994,83:3753-7.
108. Teramura M, Kobayashi S, Iwabe K, et al: Mechanism of action of antithymocyte globulin in the treatment of aplastic anaemia: In vitro evidence for the presence of immunosuppres sive mechanism. Pr J Haematol 1997,96:80-84,
109. Hershko C, Ho WG, Gale RP, Cline MJ. Cure of aplastic anemia in paroxysmal nocturnal hamoglobinuria by marrow transfusion from identical twin: failure of peripheral-leucocyte transfusion to correct marrow aplasia. Lancet 1979,1:945-7.
110. Endo M, Beatty PG, Vreeke TM, Wittwer CT, Singh SP, Parker CJ. Syngeneic bone marrow transplantation without conditioning in a patient with paroxysmal nocturnal hemoglobinuria: in vivo evidence that the mutant stem cells have a survival advantage. Blood 1996,88:742-50
111. Brett SJ, Baxter G, Cooper H, et al. Emergence of CD52-, glycosylphosphatidylinositol-anchor-defic lymphocytes in rheumatoid arthritis patients following Campath-IH treatment. Int Immunol 1995,8:325-34.
112. Taylor VC, Sims M, Brett S, et al: Antibody selection against CD52 produces a paroxysmal nocturnal haemoglobinuria phenotype in human lymphocytes by a novel mechanism. Biochem J. 1997,322:919-925.
113. Rawstron AC, Rollinson SJ, Richards S, et al. GPIdeficient cells (PNH-phenotype) are present in most normal individuals. Blood 90:273a, 1997 (suppl 1)
114. Rawstron AC. Rollinson SJ. Richards S. et al: The PNH phenotype cells that emerge in most patients after CAMPATH-1H therapy are present prior to treatment. Br J Haematol 107:148-153, 1C)'S9
115. Luzzatto L ,Bessler M, et al.: Somatic mutation in paroxysmal nocturnal hemoglobinuria: A blessing in Disguise? Cell. 1997,88(l):l-4.
116. Araten, D. Nafa,K., Pakdeesuwan,K.,and Luzzatto L.PNH cells and GPI-Agene mutations in normal donors.Blood. 1998,92(Suppl.l):471a(Abstr.)
117. Tremml G, Dominguez C, Rostil V, et ai: Increased sensitivity to complement and a decreased red cell life span in mice mosaic for a non-functional Piga gene. Blood. 1999,94(9): 2945-54.
118. Dunn DE, Tanawattanacharoen P, Boccuni P, et al: Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes [see comments]. Ann Intern Med 1999,131:401-408.
119. Metzgar D, Wills C: Evidence for the adaptive evolution of mutation rates. Cell 101:581-584,2000.
120. Foster FL. Adaptive mutation: Implications for evolution. Bioessays2000, 22:1067-1074.121. Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med 1997,336:1365-1372.
122. Sloand EM, Fuhrer M, Keyvanfar K, et al. Cytogenetic abnormalities in paroxysmal nocturnal haemoglobinuria usually occur in haematopoietic cells that are glycosylphosphatidylinositol-anchored protein (GPI-AP) positive. Br J Haematol. 2003,123(1):173-6.
123. Sholar PW, Bell WR. Thrombolytic therapy for inferior vena cava thrombosis in paroxysmal nocturnal hemoglobinuria. Ann Intern Med 1985,103:539-541.
124. Bourantas K, High dose recombinant human erythropoietin and low-dose corticosteroids for treatment of anemia in paroxysmal nocturnal hemoglobinuria. Acta Hematol. 1994,91:62-65.
125. Schaefer A, Jasinski M, Bessler M. High-dose cyclophosphamide does not eradicate paroxysmal nocturnal haemoglobinuria haematopoiesis in mice carrying a Piga gene mutation. Br J Haematol. 2003, 120(5):903-6.
126. Raiola AM, Van Liny MT, Lamparelli T, et al.: Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria Haematol. 2000,85:59-62.
127. Griscelli-Bennaceur A, Gluckman E , Scrobohaci ML, et al.: Aplastic anemia and paroxysmal nocturnal hemoglobinuria: search for a pathogenetic link. Blood 1995,85:1354-1363.
128. Nafa K, Bessler M, Deeg HJ, et al. New somatic mutation in the PIG-A gene emerges at relapse of paroxysmal nocturnal hemoglobinuria. Blood 1998,92:3422-7.
129. Graham MI,, Rosse WE Halperin EC, et al: Resolution of Budd-Chiari syndrome following bone marrow transplantation for paroxysmal nocturnal hemoglobinuria. Br J Haematol 1996,92:707-710.
130. Doukas MA, Fleming D, Jennings D, Identical twin marrow transplantation for venous thrombosis in paroxysmal nocturnal hemoglobinuria: long term complete remission as assessed by flow cytometry. Bone marrow transplant 1998,22:717-721.
131. Mcmullin MF, Hillmen P, Jacson J, et al. Tissue plasminogen activator for hepatic vein thrombosis in paroxysmal nocturnal hemoglobinuria.J Intern Med. 1994: ,235:85-89.
132. Hillmen P, Hall C, Marsh JC, et al., Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. Engl J Med. 2004 Feb 5; 350(6):552-9.
133. Spitzer D, Unsinger J, Bessler M, Atkinson JP. ScFv-mediated in vivo targeting of DAF to erythrocytes inhibits lysis by complement. Mol Immunol. 2004, 40(13): 911-9.1 Boccuni P, Vecchio Del, et al. Glycosyl-phosphatidylinositol(GPI)-anchored molecues and the pathogenesis of paroxysmal nocturnal hemoglobinuria. Crit Rev Oncol Hematol, 2000, 33: 25-43.
2 Frickhofen N, Kaltwasser JP, Schrezenmeier H, et al. Treatment of aplastic anemia with antithymocyte globulin and methylprednisolone with or without cyclosporin. N Engl J Med, 1991, 324: 1297-1304.
3 Rosenfeld SE, Kimball J, Vining D, et al. Intensive immunosuppression with antithymocyte globulin and cyclosporin as treatment for severe acquire aplastic anemia, Blood, 1995, 85: 3058-65.
4 Schubert C, Scholz C. Ggeissler RG, et al. G-CSF and cyclosporin induce an increase of normal cells in paroxysmal nocturnal hemoglobinuria, Ann Hematol, 1997, 74: 225-230.
5 Stoppa AM, Vey N, Sainty D, et al. Correction of aplastic anaemia complicating paroxysmal nocturnal hemoglobinuria: absence of eradication of the PNH clone and dependence of response on cyclosporin A administration. Br J Haematol, 1996, 93: 42-44.
6 Kamp H, Imhoff GW, Wolf JT, et al. The effect of cyclosporin on haematologial parameters in patients with paroxysmal nocturnal hemoglobinuria. Br J Haematol, 1995, 89: 78-82.
7 Packman C H. Pathogenesis and management of paroxysmal nocturnal hemoglobinuria, Blood Reviews, 1998, 12: 1-11.
8 Ronald L. Paquette, Ryan Yoshimura, Charles Vbiseh, et al. Clinical characteristics predict response to antithymocyte globulin in paroxysmal nocturnal hemoglobinuria, Br J Haematol, 1997, 96: 92-97.
9 Schrezenmeier H. Hertenstein B, Wagner B, et al. A pathogenetic link between aplastic anemia and paroxysmal nocturnal hemoglobinuria is suggested by high frequency of aplastic anemia patients with a deficiency of glycosylphosphatidilinositol anchored protein. Exp Hematol, 1995, 23: 81-87
10 Brodsky RA, Sensenbrenner LL, Jones RJ. Complete remission in severe aplastic anemia after high-dose cyclophasphomide without bone marrow transplantation. Blood, 1996, 87: 491-494.
11 Endo M, Beatty PG, Vreeke TM, et al. Syngeneic bone marrow transplantation without conditioning in a patient with paroxysmal nocturnal haemoglobinuria: in vivo evidence that the mutant stem cells have a survival advantage. Blood, 1996, 88: 742-750.
12 邵宗鸿，赵明峰，李克，等低剂量联合化疗对难治性、复发性阵发性睡眠性血红蛋白尿的疗效观察 中国实用内科杂志，2000，20：607-609．
13 Bemba M, Guradiola P, Garderet LU, et al. Bone marrow transplantation for paroxysmal nocturnal haemoglobinuria. Br J Haematol; 1999, 105: 366-368.
14 Suenaga K, Kanda Y, Niiya H, et al. Successful application of nonmyeloablative transplantation for paroxysmal nocturnal hemoglobinuria, Exp Hematol, 2001, 29: 639-642.
15 Raiola AM, van Lint Mr, Lamparelli r. Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria. Haematologica 2000, 85: 59-62,16 Saso R, March J, Cevreska L, et al. Bone marrow transplantation for paroxysmal nocturnal haemoglobinuria. Br J Haematol, 1999, 104:392-396.
17 Woodard P, Wang W, Pitts N, et al. paroxysmal nocturnal hemoglobinuria successful unrelated donor bone marrow transplantation for paroxysmal nocturnal hemoglobinuria,Bone Marrow Transplant,2001, 27:589-592.
18 Champlin RE, Feig SA, Sparkes RS, et al. Bone marrow transplantation from identical twins in the treatment of aplastic anemia: implication for the pathogenesis of the disease. Br J Haematol,1984,56:455-463.
19 Kolb HJ, Holler E, Bender-Gotze C, et al. Myeloablative conditioning for marrow transplantation in myelodysplastic syndromes and paroxysmal nocturnal haemoglobinuria. Bone Marrow Transplant,1989, 4:29-34.
20 Luzzatto L, Bessler M. The duel pathogenesis of paroxysmal nocturnal hemoglobinuria. Curr Opin Hematol 1996,3:101-110.
21 Mikhailova EA, Turbina NS,et al. Cytostatic threapy in paroxysmal nocturnal hemoglobinuria. Probl Gemato Prereliv Krovi.1979, 24(8):38-41.
2. Socie G, Mary JY, de Gramont A, et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet. 1996,348:573-7.
3. Hilmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995, 333:1253-8.
4. Ware RE, Hall SE, Rosse WF. Paroxysmal nocturnal haemoglobinuria with onset in childhood and adolescence. N Engl J Med. 1992, 325:991-996.
5. Rotoli B, Luzzatto L, Baillieres. Paroxysmal nocturnal haemoglobinuria. Clin Haematol. 1989,2:113-38.
6. Harris JW, Koscick R, Lazarus HM, et al. Leukemia arising out of paroxysmal nocturnal hemoglobinuria. Leuk Lymphoma. 1999,32:401-426.
7. Davitz MA, Low MG, Nussenzweig V. Release of decay-accelcrating factor (DAF) from the cell membrane by phosphatidylinositol-specific phospholipase C (PIPLC). Selective modification of a complement regulatory protein. J Exp Med. 1986, 163: 1150-61.
8. Bessler M, Hilmen P. Somatic mutation and clonal selection in the pathogenesis and in the control of paroxysmal nocturnal haemoglobinuria. 1998, 35(2): 149-67.
9. Rosse WF. Variations in the red cells in paroxysmal nocturnal haemoglobinuria. Br J Haematol. 1973,24:327-342.
10. Wendell F.Rosse New insights into paroxysmal nocturnal hemoglobinuria, Current Opinion in Hematology. 2001,8:61-67.
11.Maciejewski JP, Sloand EM, Sate T, et al. Impaired hematopoiesis in paroxysmal nocturnal hemoglobinurialaplastic anemia is not associated with a selective proliferative defect in the glycosylphosphatidylinositol-anchored protein-deficient clone. Blood, 1997, 89:1173-81.
12. Tseng JE, Hall SE, Howard TA, et al. Phenotypic and functional analysis of lymphocytes in paroxysmal nocturnal hemoglobinuria. Am J Hematol, 1995, 50: 244-53.
13. Rosti V, Tremml G, Soares V, et al. Embryonic stem cells without PIG-A gene activity are competent for hematopoieis with the PNH phenotype but notfor clonal expansion. J Clin Invest. 1997, 100:1028-1036.
14. Xiao J, Wu YJ, Zhang ZN, et al. Application of double immunomagnetic positive sorting to ex vivo expansion of marrow CD34(+) CD59(+) cells from patients with paroxysmal nocturnal hemoglobinuria. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2003, 11(2): 179-83.
15. Clark DA, Butler SA. Bessler M, et al. The kidneys in paroxysmal nocturnal hemoglobinuria. Blood. 1981,57:83-891. Karadimitris, Luzzatto L. The cellular pathogenesis of paroxysmal nocturnal hemoglobinuria. Leukemia, 2001, 15: 1148-1152.
2．邵宗鸿，赵明峰，李克，等 低剂量联合化疗对难治性、复发性阵发性睡眠性血红蛋白尿的疗效观察．中国实用内科杂志，2000，20：607-609．
3．张之南，沈悌，主编．血液病诊断及疗效标准．第2版．北京：北京科学出版社，1998．33-36．
4. Alfinito F, lo Pardo C, Boccuni P, et al. Reliable identification of the PNH defect on lymphocyte and monocyte membrane by CD48 MoAbs, In: Kishimoto T, Kikutani I-I, von dem Borne AEG, et al. eds. Leukocyte Typing Ⅵ. New York: Garland Publishing, 1997. 512-514.
5. Rosti V, Tremml G, Soares V, et al. Embryonic stem cells without PIG-A gene activity are competent for hematopoieis with the PNH phenotype but not for clonal expansion. J Clin Invest. 1997, 100: 1028-1036.
6. Taylor VC, Sims M, Brett S, et al. Antibody selection against CD52 produces a paroxysmal nocturnal haemoglobinuria phenotype in human lymphocytes by a novel mechanism. Biochem J. 1997, 322: 919-925.
7. Boccuni P, del Vecchio L, di Noto R, et al. Glycosyl-phosphatidylinositol (GPI)-anchored molecues and the pathogenesis of paroxysmal noctumal hemoglobinuria. Crit Rev Oncol Hematol. 2000, 33: 25-43.
8. Araten DJ, Nafa K, et al. Clonal populations of hematopoietic cells with paroxysmal noctumal hemoglobinuria genotype and phenotype are present in normal individuals. Proc. Natl. Acad. Sci. USA. 1999, 96(9): 5209-5214。1. Glycosyl-phosphatidylinositol(GPI)-anchored molecules and the pathogenesis of paroxysmal nocturnal hemoglobinuria. Hematology. 2000, 33: 25-43.
2. Fujioka S, Asai T. Prognostic features of paroxysmal nocturnal hemoglobinuria in Japan. Nippon Ketsueki Gakkai Zasshi. 1989, 52: 1386-94.
3. Zhang Z, Liu EK. Experiences in clinical diagnosis of paroxysmal noctumal hemoglobinuria. Chung Hua Nei Ko Tsa Chih. 1995, 34: 540-4.
4. Lu JC, Lin MT. Paroxysmal nocturnal hemoglobinuria: report of one case. Chung Hua Min Kuo Hsiao Erh Ko I Hsueh Hui Tsa Chih. 1989, 30: 323-5.
5. Le XF, Yang TY, Yang XY, Wang XM. Characteristics of paroxysmal nocturnal hemoglobinuria in China. Clinical analysis of 476 cases. Chin Med J. 1990, 103: 885-9.
6. Tseng JE, Hall SE, Howard TA, Ware RE. Phenotypic and functional analysis of lymphocytes in paroxysmal noctumal hemoglobinuria. Am J Hematol. 1995, 50: 244-53.
7. Tumen J, Kline LB, Fay JW, et al. Complement sensitivity of paroxysmal nocturnal hemoglobinuria bone marrow cells. Blood 1980, 55: 1040-6.
8. Maciejewski JP, Sloand EM, Sate T, et al. Impaired hematopoiesis in paroxysmal noctumal hemoglobinurialaplastic anemia is not associated with a selective proliferative defect in the glycosylphosphatidylinositol-anchored protein-deficient clone. Blood 1997, 89: 1173-81.
9. Nishimura J., Ware R. E., Bumette A., et al. The hematopoietic defect in PNH is not due to defective stroma but is due to defective progenitor cells. Blood Cells, Molecules & Diseases. 2002a, 29, 159-167.
10．肖娟，武永吉，张之南，等，阵发性睡眠性血红蛋白尿症患者骨髓CD34+CD59+细胞与CD34+CD59-细胞生物学性能的研究，中华血液学杂志，2003，第24卷，第4期，169-173．Chin J Hematol．April 2003，24，No．4，169-173．
11. Rosti V, Tremml G, Soares V, et al. Embryonic stem cells without PIG-A gene activity are competent for hematopoieis with the PNH phenotype but not for clonal expansion. J Clin Invest. 1997, 100: 1028-1036.
12. Kawagoe K, Kitarnura D, Okabe M, et al. Glycosylphos-phatidylinositol-anchor-deficient mice: implications for clonal??dominance of mutant cells in paroxysmal nocturnal hemoglobinuria. Blood 1996, 87:3600-6.
13.Tarutani M, itami S, Okabe M, et al. Issue-specific knockout of the mouse PIG-A gene reveals important roles for GPI-anchored: proteins in skin development. Proc Natl Acad Sci USA 1997,94:7400-5.
14.Tremml G, Dominguez C, Rostil V, et al: Increased sensitivity to complement and a decreased red cell life span in mice mosaic for a non-functional Piga gene. Blood. 1999, 94: 2945-54.
15.Murakami Y, Kinoshita T, Maeda Y, et al: Different roles of glycosylphosphatidylinositol in various hematopoietic cells as revealed by a mouse model of paroxysmal nocturnal hemoglobinuria [see comments]. Blood 1999,94:2963-2970.
16．孙卫民,王惠琴编著《细胞因子研究方法学》：p633—643
17.Schubert J, Scholz C, Geissler RG. G-CSF and cyclosporin induce an increase of normal cells in hypoplastic paroxysmal nocturnal hemoglobinuria. Ann Hematol. 1997 ,74(5):225-30.
18.Prince GM, Mguyen M, Lazarus HM., et al Brodsky RA, Terstappen LWMM, Medof E. Peripheral blood harvest of unaffected CD34+/CD38- hematopoietic precursors in paroxysmal nocturnal hemoglobinuria. Blood 1995; 86: 3381-3386.
19.Fujimi A, Matsunaga T, Kogawa K, et al, A patient with paroxysmal nocturnal haemoglobinuria in whom granulocyte colony-stimulating factor administration resulted in improvement of recurrent enterocolitis and its associated haemolytic attacks British Journal of Haematology, 2002, 119, 858-862.
20.Jego P, Le Strat A, Girard L, et al, Paroxysmal Nocturnal Hemoglobinuria: Efficacy of Prolonged Treatment With Granulocyte Colony-Stimulating Factor,Blood. 1997 Oct 1;90(7):2841-3.
21.Johnson RJ, Rawstron AC, Richards S, et al, Circulating Primitive Stem Cells in Paroxysmal Nocturnal Hemoglobinuria (PNH) Are Predominantly Normal in Phenotype But Granulocyte Colony-Stimulating Factor Treatment Mobilizes Mainly PNH Stem Cells. Blood, 91, No 12, 1998: 4504-4508.1．施均，骨髓增生异常综合征细胞周期异常及细胞周期调控基因表达谱的研究(博士学位论文)，p．54．
2. Shao Z, Zhang H, Chen G, et al. Expression and function of c-kit receptor in bone marrow mononuclear cells of patients with myelodysplastic syndromes. Chin Med J(Eng1). 2001, 114(5): 481-5.
3．孙卫民，王惠琴编著《细胞因子研究方法学》，p．633-669．
4. Michael K. Richards, Fulu Liu, Hiromi Iwasaki, et al., Pivotal role of granulocyte colony-stimulating factor in the development of progenitors in the common myeloid pathway. Blood. 2003, 102: 3562-3568.
5. JenniferA. L, Terrye E. P, William M. M, Evaluation of Cytokines for Expansion of the Megakaryocyteand Granulocyte Lineages, Stem Cells. 1997, 15: 198-206
6. K. Matsumura-Takeda, K. Kotosai, A. Ozakia, et al. Rat granulocyte colony-forming unit(CFU-G) assay for the assessment of drug-induced hematotoxicity. Toxicology in Vitro 16.2002, 281-288.
7. Small D, Levenstein M, Kim E, et al. STK-1, the human homologue of F1k-2/F1t-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci USA. 1994, 91: 459-63.
8. Rosnet O, Birnbaum D. Hematopoietic receptors of class Ⅲ receptor-type tyrosine kinases. Crit Rev Oncog. 1993, 4: 595-613.
9. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990, 6: 203-12.
10. Andre C, d'Auriol L, Lacombe C, et al. c-kit mRNA expression in human and murine hematopoietic cell lines. Oncogene. 1989, 4: 1047-9.
11. Hu ZB, Ma W, Uphoff CC, et al. c-kit expression in human megakaryoblastic leukemia cell lines. Blood. 1994, 83: 2133-44.
12. deCastro CM, Denning SM, Langdon S, et al. The c-kit proto-oncogene receptor is expressed on a subset of human CD3-CD4-CD8-(triple-negative) thymocytes. Exp Hematol. 1994, 22: 1025-33.
13. Gunji Y, Nakamura M, Osawa H, et al. Human primitive hematopoietic progenitor cells are more enriched in KIT low cells than in KIT high cells.??Blood. 1993, 82:3283-9.
14. Lammie A, Drobnjak M, Gerald W, et al. Expression of c-kit and kit ligand proteins in normal human tissues.J Histochem Cytochem. 1994, 42:1417-25.
15. Chui X, Egami H, Yamashita J, et al. Immunohistochemical expression of the c-kit proto-oncogene product in human malignant and non-malignant breast tissues. Br J Cancer. 1996, 73:1233-6.
16. Hibi K, Takahashi T, Sekido Y, et al. Coexpression of the stem cell factor and the c-kit genes in small-cell lung cancer. Oncogene. 1991, 6:2291-6.
17. Sekido Y, Takahashi T, Ueda R, et al. Recombinant human stem cell factor mediates chemotaxis of small-cell lung cancer cell lines aberrantly expressing the c-kit protooncogene. Cancer Res. 1993, 53:1709-14.
18. Krystal GW, Hines SJ, Organ CP. Autocrine growth of small cell lung cancer mediated by coexpression of c-kit and stem cell factor. Cancer Res. 1996, 56:370-6.
19. Hines SJ, Organ C, Kornstein MJ, et al. Coexpression of the ckit and stem cell factor genes in breast carcinomas. Cell Growth Differ. 1995, 6:769-79.
20. Ohashi A, Funasaka Y, Ueda M, et al. c-kit receptor expression in cutaneous malignant melanoma and benign melanotic naevi. Melanoma Res 1996, 6:25-30.
21. Turner A M, Zsebo KM, Martin F, et al. Nonhematopoietic tumor cell lines express stem cell factor and display c-kit receptors. Blood. 1992, 80:374-81.
22. Cascavill N, Pellegrino M, D' Arena G, et al. Cd117 (c-Kit) is a restricted antigen of acute myeloid leukemia and characterizes early differentiative levels of M5 FAB subtype. Hematologica. 1998, 83: 392-397.
23. Reilly JT. Receptor tyrosine kinases in normal and malignant haematopoiesis. Blood Rev. 2003 Dec, 17:241-8.
24. Mol CD, Lim KB, Sridhar V, et al. Structure of a c-kit product complex reveals the basis for kinase transactivation. J. Biol. Chem. 2003, 278: 31461-31464.
25. Ashman LK, Cambareri AC, To LB, et al. Expression of the YB5.B8 antigen (c-kit proto-oncogene product) in normal human bone marrow. Blood. 1991, 78:30-7.
26. BENE MC, BERNIER M, CASASNOVAS RO, et al. The European Group for the Immunological Classi?cation of Leukemias (EGIL). The reliabilityand speci?city of c-kit for the diagnosis of acute myeloid leukemias and undifferentiated leukemias. Blood 1998,92:596-599.
27. BUE HRING HJ, ULLRICH A, SCHAUDT K, et al. The product of the proto-oncogene c-kit (P145c-kit) is a human bone marrow surface antigen of hemopoietic precursor cells which is expressed on a subset of acute non-lymphoblastic leukemic cells. Leukemia 1991,5: 854-860.
28. REUSS-BORST MA, BUE HRING HJ, SCHMIDT H, MUE LLER CA. AML: immunophenotypic heterogeneity and prognostic signi?cance of c-kit expression. Leukemia 1994,8:258-263.
29. Morita S, Tsuchiya S, Fujie H, et al. Cell surface c-kit receptors in human leukemia cell lines and pediatric leukemia: selective preservation of c-kit expression on megakaryoblastic cell lines during adaptation to in vitro culture. Leukemia 1996, 10:102-5.
30. Ashman LK, Buhring HJ, Aylett GW, et al. Epitope mapping and functional studies with three monoclonal antibodies to the c-kit receptor tyrosine kinase, YB5.B8, 17F11, and SR-1. J Cell Physiol 1994, 158:545-54.
31. Siitonen T, Savolainen ER, Koistinen P. Expression of the c-kit protooncogene in myeloproliferative disorders and myelodysplastic syndromes. Leukemia 1994, 8:631-7.
32. Muroi K, Nakamura M, Amemiya Y, et al. Expression of c-kit receptor (CD117) and CD34 in leukemic cells. Leuk Lymphoma 1995, 16:297-305.
33. Sincock PM, Ashman LK. Expression of c-Kit and functional drug efflux are correlated in de novo acute myeloid leukemia. Leukemia 1997, 11: 1850-1857.
34. Bendall LJ, Makrynikola V, Hutchinson A, et al. Stem cell factor enhances the adhesion of AML cells to fibronectin and augments fibronectin-mediated anti-apoptotic and proliferative signals. Leukemia 1998, 12: 1375-1382.
35. Scolnic MP, Morilla R, de Bracco MM, et al. CD34 and CD117 are overexpression in AML may be valuable to detect minimal residual disease. Leuk Res 2002, 26: 615-619.
36. Wozniak J, Kopec-Szlezak J. C-Kit receptor (CD 117) expression on myeloblasts and white blood cell counts in acute myeloid leukemia. Cytometry. 2004, Mar, 58B(1): 9-16.
37. Rotoli B, Luzzatto L. Paroxysmal nocturnal haemoglobinuria. Baillieres. Clin??Haematol. 1989,2:113-38.
38. Harris JW, Koscick R, Lazarus HM, et al. Leukemia arising out of paroxysmal nocturnal hemoglobinuria. Leuk Lymphoma. 1999,32:401-426.1. Malech H. L, J I Gallin. Neutrophils in human diseases. N Engl J Med. 1987,317:687.
2. Weiss, S. J. Tissue destruction by neutrophils. N Engl J Med. 1989, 320:365.
3. Savill J S, A H Wyllie, J E Henson, et al. Macrophage phagocytosis of aging neutrophils in inflammation-programmed cell death in the neu-trophil leads to its recognition by the macrophages. J. Clin. In-vest. 1989, 83:865.
4. Meagher L C, J S Savill, A Baker, et al. Phagocytosis of apoptotic neutrophils does not induce macro- phage release of thromboxane. Leukocyte Biol. 1992,52:269.
5. Whyte M. B., L. C. Meagher, J. MacDermot, et al. Impairment of function in aging neutrophils is associated with ap- optosis. J. Immunol. 1993,150:5124.
6. Ravetch JV, Perussia B. Alternative membrane forms of Fc RIII (CD 16) on human natural killer cells and neutrophils. J Exp Med. 1989,170:481-497.
7. Crockett T E, Smith CW, Kateley JR. et al. Insoluble immune complex-stimulated neutrophil leukotriene B4 production is dependent on FcyRII and FcyRIII and independent of pertussis toxin-sensitive signal transduction pathways. Am J Pathol. 1992, 140:613.
8. Hundt M, Schmidt RE. The glycosylphosphatidylinositollinked Fcγ receptor III represents the dominant receptor structure for immune complex activation of neutrophils. Hannover, Germany, Hannover Medical School. Eur J Immunol. 1992,22:811.
9. Brunkhorst B. A., G. Strohmeier, K. Lazzarin, et al. Differential roles of Fc Y R II and Fc Y R III in immune complex stimulation of human neutrophils. J. Biol. Chem. 1992, 29:20659.,
10. Zhou M. J., R. F. Todd, J. G. J. van de Winkel, et al. Cocapping of the leukoadhesin molecules complement receptor type 3 and lymphocyte function-associated antigen-1 with Fc-receptor III on human neutrophils. J. Immunol. 1993, 150:3030.
11. Schubert J, Vogt HG, Zielinska-Skowronek M, et al. Development of the glycosylphosphatitylinositol-anchoring defect characteristic for paroxysmal nocturnal hemoglobinuria in patients with- aplastic anemia. Blood. 1994,83:2323-8.
12. Hundt M, Jorg Schubert, Masja de Haas, et al. The Loss of FcyRIIIb in??Paroxysmal Nocturnal Hemoglobinuria Is Functionally Replaced by FcyRII. Blood. 1994,Vol83,No 12,3574-3580.
13. Ian Dransfield, Anne-Marie Buckle, et al. Neutrophil Apoptosis Is Associated with a Reduction in CD 16 (FcyRIII) Expression. The Journal of Immunology, 1994, 153: 1254.
14. Brach MA, de Vos S, Gruss HJ, et al. Prolongation of survival of human polymorphonuclear neutrophils by granulocytemacrophage colony-stimulating factor is caused by inhibition of programmed death. Blood. 1992, 80:2920.
15. Chitinis D, Dickerson C, Munster AM, et al. Inhibition of apoptosis in polymorphonuclear neutrophils from burn patients. J Leukoc Bio. 1996, 59:835.
16. Christa H E, Masja de Haas, Albert E.G.Kr, et al. Human Neutrophils Lose Their Surface FcyRIII and Acquire Annexin V Binding Sites During Apoptosis In Vitro. Blood. 1995, 85, 532-540.
17. Boros P., Odin J. A., Chen J., et al. Specificity and class distribution of FcgR-specific autoantibodies in patients with autoimmune disease. J. Immunol. 1994, 152,302-306.
18. Lamour A., Le Corre R., Pennec Y. L., et al. Heterogeneity of neutrophil antibodies in patients with primary Sjo|¨gren's syndrome. Blood .1995,86, 3553-3559.
19. Lamour A., Baron D., Soubrane C, et al. Anti-Fc gamma receptor III autoantibody is associated with soluble receptor in rheumatoid arthritis serum and synovial fluid. J. Autoimmun. 1995,8: 249-265.
20. Veronique Durand, Yves Renaudineau, Jacques-Olivier Pers, et al. Human FcγRIIIb Induces the Production of Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor by Polymorphonuclear Neutrophils. J Immunol. 2001, 167(7): 3996-4007.
21.Weinmann P., P. Gaehtgens B. Walzog. Bcl-x_L and Bax-α-mediated regulation of human neutrophils via caspase-3. Blood. 1999,93:3106.
22. Liles WC, Klebanoff SJ. Regulation of apoptosis in neutrophils-Fas track to death? J Immunol. 1995,155(7): 3289-91.
23. Issaragrisil S, U-pratya Y, Yimyam M, et al. Hematopoitic progenetor cells in the blood and marrow in various hematologic disorders. Stem Cells. 1998,16:123-128.24. Chen G., Kirby M., Zeng W., et al. Superior growth of glycophosphatidylinositol-anchored protein-deficient progenitor cells in vitro is due to the higher apoptotic rate of progenitors with normal phenotype in vivo. Experimental Hematology. 2002, 30: 774-782.
25. Brodsky R.A., Vala M.S., Barber J.P., et al. Resistance to apoptosis caused by PIG-A gene mutations in paroxysmal nocturnal hemoglobinuria. Proceedings of the National Academy of Sciences. 1997, 94:8756-8760.
26. Bessler M. Paroxysmal nocturnal hemoglobinuria: insights from resent advances in molecular biology. Transfusion Medicine Reviews.2001, Vol 15,255-267.
27. Ware RE, Nishimura J, Moody MA, et al. The PIG-A mutation and absence of glycosylphosphatidylinositol-linked proteins do not confer resistance to apoptosis in paroxysmal nocturnal hemoglobinuria. Blood. 1998,2541-2550.
28. Horikawa K, Nakakuma H, Kawaguchi T, et al. Apoptosis resistance of blood cells from patients with paroxysmal nocturnal hemoglobinuria, aplastic anemia, and myelodysplastic syndrome. Blood 1997,90:2716-22.
29. J. C. W. Marsh, M. O. Elebute, Stem cells in paroxysmal nocturnal haemoglobinuria and aplastic anaemia: increasing evidence for overlap of haemopoietic defect. Transfusion Medicine. 2003, 13(6), 377.
1. Glycosyl-phosphatidylinositol(GPI)-anchored molecues and the pathogenesis of paroxysmal nocturnal hemoglobinuria. Hematology. 2000, 33:25-43.
2. Strubing P. Paroxysmale Hlmoglobinurie. Dtsch Med Wochenschr 1882;8:1.
3. Karadimitris, Luzzatto L, The cellular pathogenesis of paroxysmal nocturnal hemoglobinuria. Leukemia. 2001, 15: 1148-1152.
4. Socie G, Mary JY, de Gramont A, et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet. 1996,348:573-7.
5. Hilmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995, 333:1253-8.
6. Ware RE, Hall SE, Rosse WF: Paroxysmal nocturnal haemoglobinuria with onset in childhood and adolescence. N Engl J Med. 1992, 325:991-996.
7. Rotoli B, Luzzatto L. Paroxysmal nocturnal haemoglobinuria.Baillieres. Clin Haematol. 1989,2:113-38.
8. Harris JW, Koscick R, Lazarus HM, et al. Leukemia arising out of paroxysmal nocturnal hemoglobinuria. Leuk Lymphoma. 1999,32:401-426.
9. Cowall DE, Pasquale DN, Dekker P. Paroxysmal nocturnal hemoglobinuria terminating as erythroleukemia. Cancer. 1979,43:1914-6.
10. Carmel R, Coltman CA, Yatteau RF, Costanzi JJ. Association of paroxysmal nocturnal hemoglobinuria with erythroleukemia. N Engl J Med. 1970,283:1329-31.
11. Zittoun R, Bernadou A, James JM, Soria J, Bousser J. Acute myelo-monocytic leukaemia: a terminal complication of paroxysmal nocturnal haemolobinuria. Acta Haematol. 1975,53:241-8.
12. Graham DL, Gastineau DA, Paroxysmal nocturnal hemoglobinuria as a marker for clonal myelopathy. Am J Med. 1992,93:671 -4.
13. Meri S, Morgan BP, Davies A, et al. Human protectin (CD59), an 18 000-20 000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers. Immunofogy 1990;71: 1-9.
14. Wendell F., Rosse ,Russell E.Ware, The molecular basis of paroxysmal nocturnal hemoglobinuria. Blood, 1995, 86:3277-3286.
15. Zupanska B, Uhrynowska M, Konopka L. Transfusion-related acute lung injury due to granulocyte-agglutinating antibody in a patient with paroxysmal nocturnal hemoglubinuria.Transfution. 1999,39:944-977.
16. Clark DA, Butler SA. Bessler M, et al. The kidneys in paroxysmal nocturnal hemoglobinuria. Blood. 1981,57:83-89.
17. Hartmann RC, Bruce ASC. Fetomaternal outcomes of pregnancy in paroxysmal nocturnal hemoglobinuria. In Hematologic Disorders in Maternal-Feternal Medicine. New York, Wiley-Liss; 1993:261 -281.
18. Wiedmer T, Hall SE. , Ortel TL. Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria and aplastic anemia.Blood 1993,82:1192-1196.
19. Hugel B, Socie G, Vu T,et al. elevated levels of circulating procogulant microparticles in parients with paroxysmal nocturnal hemoglobinuria and aplastic anemia.Blood1999,93:3451-3464.
20. Hamilton KK, Hattori R, Esmon CT, Sims PJ. Complement proteins C5b-9 induce vesiculation of the endothelial plasma membrane and expose catalytic surface for assembly of the prothrombinase enzyme complex. J Biol Chem 1990;265:3809-14.
21. Wendell F.Rosse New insights into paroxysmal nocturnal hemoglobinuria, Current Opinion in Hematology 2001,8:61-67.
22. Ploug M, Plesner T, Ronne E, Ellis V, Hoyer-Hansen G,Hansen NE, et al. The receptor for urokinase-type plasminogen activator is deficient on peripheral blood leukocytes in patientswith paroxysmal nocturnal hemoglobinuria.Blood. 1992, 79: 1447-55.
23. Moiler LB. Structure and function of the urokinase receptor.Blood Coagul Fibrinol 1993;4:293-303.
24. Liebman HA. , Feinstein DI. , Thrombosis in patients with paroxysmal noctural hemoglobinuria is associated with markedly elevated plasma levels of leukocyte-derived tissue factor. Thromb Res. 2003, 111(4-5):235-8.
25. Hall C, Richards S, Hillmen P., Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2003, 102:3587-91.
26. Fujioka S, Asai T. Prognostic features of paroxysmal nocturnal hemoglobinuria in Japan. Nippon Ketsueki Gakkai Zasshi. 1989,52: 1386-94.
27. Zhang Z, Liu EK. Experiences in clinical diagnosis of paroxysmal nocturnal hemoglobinuria. Chung Hua Nei Ko Tsa Chih.1995, 34:540-4.
28. Lu JC, Lin MT. Paroxysmal nocturnal hemoglobinuria: report of one case. Chung Hua Min Kuo Hsiao Erh Ko I Hsueh Hui Tsa Chih. 1989,30:323-5.
29. Le XF, Yang TY, Yang XY, Wang XM. Characteristics of paroxysmal nocturnal hemoglobinuria in China. Clinical anaiysis of 476 cases. Chin Med J. 1990,103:885-9.
30. Davitz MA, Low MG, Nussenzweig V. Release of decay-accelcrating factor (DAF) from the cell membrane by phosphatidylinositol-specific phospholipase C (PIPLC). Selective modification of a complement regulatory protein. J Exp Med 1986,163: 1150-61.
31. Ham TH, Dingle JH. Studies on the destruction of red blood cells. II. Chronic hemolytic anemia with paroxysmal nocturnal hemoglobinuria: certain immunological aspects of the hemolytic mechanism with special reference to serum complement. J Clin Invest 1938,18:657-72.
32. Hartmann RC, Jenkins DJE: The "suger water" test for paroxysmal nocturnal hemoglobinuria. New Engl J Med. 1996,275:155-155.
33. Rosse WF, Dacie JV: Immune lysis of paroxysmal nocturnal hemoglobin red blood cells.I.The sensitivity of PNH red cells to lysis by complement and specific antibody. J Clin Invest 1966,45:736-748.
34. Hall S, Rosse WF: The use of monoclonal antibody and flow cytometry in the diagnosis of paroxysmal nocturnal hemoglobinuria. Blood 1996, 87:5332-5340.
35. Richard SJ, Rawstron AC, Hilmen P: Application of flow cytometry in the diagnosis of paroxysmal nocturnal hemoglobinuria. Cytometry.2000,42:223-233.
36. Van der Schoot CE, Huizinga TW, van't Veer-Korthof ET, W1 Jmans R, Pinkster J, von dem Borne AE. Deficiency of glycosyl-phosphatidylinositol-linked membrane glycoproteins of leukocytes in paroxysmal nocturnal hemoglobinuria, description of a new diagnostic cytofluorometric assay . Blood 1990, 76: 1 853 -9.37. Plesner T, Hansen NE, Carlsen K. Estimation of Pi-bound proteins on blood cells from PNH patients by quantitative flow cytometry. Br J Haematol 1990,75:585-90.
38. Schubert J, Vogt HG, Zielinska-Skowronek M, Freund M. Kaltwasser JP, Hoelzer D, et al. Development of the glycosylphosphatitylinositol-anchoring defect characteristic for paroxysmal nocturnal hemoglobinuria in patients with- aplastic anemia. Blood 1994,83:2323-8.
39. Nakakuma H, et al. Paroxysmal nocturnal hemoglobinuria clone in bone marrow of patients with pancytopenia. Blood 1995,85: 1371-6.
40. Alfinito F, Lo Pardo C, Boccuni P, Pandolfi G, Del Vecchio L and Rotoli B. Reliable identification of the PNH defect on lymphocyte and monocyte membrane by CD48 MoAbs, In: Kishimoto T, Kikutani I-I, von dem Borne AEG et al., editors. Leukocyte Typing VI. New York: Garland Publishing, 1997,. 512-514.
41. Krauss JS. Laboratory diagnosis of paroxysmal nocturnal hemoglobinuria. Ann Clin Lab Sci, 2003, 33: 401-6.
42. Bessler M, Hilmen P. Somatic mutation and clonal selection in the pathogenesis and in the control of paroxysmal nocturnal haemoglobinuria. 1998, 35(2):149-67.
43. Rosse WF. Variations in the red cells in paroxysmal nocturnal haemoglobinuria. Br J Haematol 24:327-342, 1973
44. Kinoshita T, Ohishi K, Takeda J. GPI-Anchor synthesis in mammalian cells gene, their products,and a deficiency.J. Biochem. 1997, 122,251-157.
45. Ferguson Mkl. Glycosyl-phosphatidylinositol membrane anchor: The tale of a tail. Biochem Soc Transactions 1992 ,20:243-256.
46. Takahashi M, Inoue N, Ohishi K, et al: PIG-B, a membrane protein of the endoplasmic reticulum with a large lurnenal domain, is involved in transfering the thrid mannose of tire GPI-anchor. EMBO J 1996,15:4254-4261.
47. Vidugiriene J, Menon AK. The GPI-anchor of cell surface proteins is synthesized on the cytoplasmatic face of the endoplasmatic reticulum. J Cell Biol 1994,127:333-341.
48. Petty HR, Todd RF. Integrins as promiscuous signal transduction devices. 1996,17:209-212.
49. Casey PJ. Protein lipidation in cell signaling. Science 1995,268:221-5.
50. Robinson PJ. Phosphatidylinositol membrane anchors and T-cell activation. Immunol Today, 1991,12:35-41
51. Stefanova I, Horsejsi V, Ansotegui U, et al. GPI anchored cell surface molecules complexed to protein tyrosine kinases Sciencel991, 254:1016-1019,
52. Brown D, Ross J. Sorting of GPI-linked; proteins to glycolipid enriched membrane subdomains during transport to the apical cell surface. Cell, 1992, 68:533-544.
53. Sargiacomo M, Sudol M, Tang Z, et al. Signal transducing molecules and glycolyl phosphatidylinositol linked proteins form a caveolin rich insoluble complex in MDCK cells. J Cell Biol 1993, 122:789-807.
54. Harder T, Simons K, Caveolae. DIGS, and the dynamics of sphingolipid-cholesteroi microdomains. Curr Opin Cell Biol, 1997, 9:534-42.
55. Anderson RGW, Kamen BA, Rotenberg KG, et al. Protocytosis: sequestration and transport of small molecules by caveolae. Science, 1992, 255:410-411.
56. Brett SJ, Baxter G, Cooper H, et al. Emergence of CD52-,glycosylphosphatidylinositol-anchor-deficient lymphocytes in rheumatoid arthritis patients following Campath-IH treatment. Int Immunol, 1996, 8:325-334.
57. Daniels G: Cromer related antigens-blood group determinants on decay acceleration factor. Vox Sang, 1989, 56:205-211.
58. Davitz MA, Hereld D, Shak S, et al: A glycanphosphatidylinositol-specific phosphoiipase D in human serum. Science, 1987, 238:81-84.
59. Cross AGM: Cellular and genetic aspects of antigenic variation in trypanosomes. Ann Rev Immunol 8:83-110, 1990 19.
60. Ueda E, Sevlever D, Prince GM, Rosenberry TL, et al. A candidate mammalian glycoinositol phospholipid precursor containing three phosphoethanolamines. J Biol Chem, 1993,268:9998-10002.
61. Ueda E, Nishimura J-I, Kitani T, et al. Deficient surface expression of glycosylphosphatidylinositol-anchored proteins in B cell lines established from patients with paroxysmal nocturnal hemoglobinuria. Int Immunol 1992;4:1263-71.
62. Hillmen P, Bessler M, Crawford DH, Luzzatto L. Production and characterization of lymphoblastoid cell lines with the paroxysmal nocturnal hemoglobinuria phenotype. Blood 1993,81:193-9.
63. Sugiyama E, DeGasperi R, Urakaze M, et al. Identification of defects in glycosylphosphatidylinositol anchor biosynthesis in the Thy-1 ex pression mutants. J Biol Chem. 1991, 266:12119-22.
64. Armstrong C, Schubert J, Ueda E, Knez JJ, Gelperin D, Hirose S, Silber R, Hollan S, Schmidt RE, Medof ME: Affected paroxysmal nocturnal hemoglobinuria T lymphocytes harbor a common defect in assembly of N-acetyl-D-gl ucosamine inositol phospholipid corresponding to that in class A Thy-1-murine lymphoma mutants. J Biol Chem 1992,267:25347.
65. Norris J, Hall S, Ware RE, Kamitani T,et al. Glycosyl-phosphatidylinositol anchor synthesis in paroxysmal nocturnal hemoglobinuria: Partial or complete defect in an early step. Blood 1994,83:816.
66. Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T, Takahashi M. Kitani T, Kinoshita T: Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell 73:703. 1993
67. Bessler M, Mason PJ, f-Iillmen P, et al. Paroxysmal nocturnal hemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. EMBO J 1994,13. 110.
68. Bessler M, Hillmen P, Longo L, et al. Genomic organization of the X-linked gene (PIG-A) that is mutated in paroxysmal nocturnal haemoglobinuria and of a related autosomal pseudogene mapped to 12q21. Hum Melee Genetl994, 3:751.
69. Bessler M. Paroxysmal nocturnal hemoglobinuria: insights from resent advances in molecular biology. Transfusion Medicine Reviews.2001, Vol 15,255-267.
70. Rollinson S, Richards S, Norfolk D, et al. Both paroxysmal nocturnal hemoglobinuria (PNH)type II cells and PNH type III cells can arise from different point mutations involving the same codon of the PIG-A gene. Blood 1997,89:3069-71.
71. Bessler M, Mason PJ, Hillmen Pet al. Somatic mutations and cellular selection inparoxysmal nocturnal haemoglobinuria. Lancet.343: 951-953.
72. Nafa K, Mason PJ, Hillmen P, et al. Mutations in the PIG-A gene causing paroxysmal??nocturnal hemoglobinuria are mainly of the frameshift type. Blood. 1995, 86:4650-5.
73. Kawagoe K, Takeda J, Endo Y, et al. Molecular cloning of murine PIG-A, a gene for GPI-anchor biosynthesis, and demonstration of interspecies conservation of its structure, function, and genetic locus. Genomics 1994,23:566-74.
74. Iida Y, Takeda J, Miyata T, et al. Characterization of genomic PIG-A gene: a gene for glycosylphosphatidylinositol-anchor biosynthesis and paroxysmal nocturnal hemoglobinuria. Blood 1994,83:3126-31.
75. Yamada N, Miyata T, Maeda K, Kitani T, Takeda J, Kinoshita T. Somatic mutations of the PIG-A gene found in Japanese patients with paroxysmal nocturnal hemoglobinuria. Blood 1995,85:885-92.
76. Nishimura J, fnoue N; Wada H, et al. A patient with paroxysmal nocturnal hemoglobinuria bearing four independent PIG-A mutant clones, Blood 1997,89:3470-6.
77. Endo M, Ware RE, Vreeke TM, et al. A patient with paroxysmal nocturnal hemoglobinuria (PNH) with an inherited mutation in PIG-A. Blood 1994,84:555a, (abstr, suppl 1).
78. Maciejewski JP, Sloand EM, Sate T, et al. Impaired hematopoiesis in paroxysmal nocturnal hemoglobinurialaplastic anemia is not associated with a selective proliferative defect in the glycosylphosphatidylinositol-anchored protein-deficient clone. Blood, 1997, 89:1173-81.
79. Tseng JE, Hall SE, Howard TA, Ware RE. Phenotypic and functional analysis of lymphocytes in paroxysmal nocturnal hemoglobinuria. Am J Hematol, 1995, 50:244-53
80. Rosti V,Tremml G, Soares V, et al. Embryonic stem cells without PIG-A gene activity are competent for hematopoieis with the PNH phenotype but not for clonal expansion. J Clin Invest. 1997, 100:1028-1036.
81. Xiao J, Wu YJ, Zhang ZN, et al. Application of double immunomagnetic positive sorting to ex vivo expansion of marrow CD34(+)CD59(+) cells from patients with paroxysmal nocturnal hemoglobinuria. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2003 ,11(2): 179-83.
82. Kawagoe K, Kitamura D, Okabe M, et al. Glycosylphos-phatidylinositol-anchor-deficient mice: implications for clonal dominance of mutant cells in paroxysmal nocturnal hemoglobinuria. Blood 1996, 87:3600-6.
83. Tarutani M, itami S, Okabe M, et al. Issue-specific knockout of the mouse PIG-A gene reveals important roles for GPI-anchored: proteins in skin development. Proc Natl Acad Sci USA 1997,94:7400-5.
84. Tremml G, Dominguez C, Rostil V, et al: Increased sensitivity to complement and a decreased red cell life span in mice mosaic for a non-functional Piga gene. Blood. 1999, 94: 2945-54.
85. Murakami Y, Kinoshita T, Maeda Y, et al: Different roles of glycosylphosphatidylinositol in various hematopoietic cells as revealed by a mouse model of paroxysmal nocturnal hemoglobinuria [see comments]. Blood 1999,94:2963-2970.
86. Wood SA, Alien ND, Rossant J, et al. Noninjection methods for the production of embryonic stem cellembryo chimaeras. Nature 1993,365:87-90.
87. Keller P.Tremml G,Rosti V, et al. X inactivation and somatic cell selection rescue female mice carrying a Piga-null mutation .Pro Natl Acad Sci U S A 1999,96:7479-7483.88. Iwamoto,N.,et al.l996.Preferential hematopoiesis by paroxysmal nocturnal hemoglubinuria clone engrafted in SCID mice.Blood.87:4944-4948.
89. Sammar M, Aigner S, Hubbe M, Schirrmacher V, Schachner M, Vestweber D, et al. Heat-stable antigen (CD24) as ligand for mouse P-selectin. Int Immunol 1994,6:1027-36.
90. Craig W, Kay R, Cutler RL, et al. Expression of Thy-1 on human hematopoietic progenitor cells. J Exp Med 1993,177:1331-42.
91. Brodsky RA.Vala MS,Barber JP,et al.: Resistance to apoptosis caused by PIG-A gene mutations in paroxysmal nocturnal hemoglobinuria.Proc Natl Acad Sci(USA) 1997,94:8756-8760.
92. Ware RE, Nishimura J, Moody MA, et al. The PIG-A mutation and absence of glycosylphosphatidylinositol-linked proteins do not confer resistance to apoptosis in paroxysmal nocturnal hemoglobinuria. Blood 1998,2541-2550.
93. Issaragrisil S, U-pratya Y, Yimyam M, et al. Hematopoitic progenetor cells in the blood and marrow in various hematologic disorders.Stem Cells 1998,16:123-128.
94. Horikawa K, Nakakuma H, Kawaguchi T, ct al. Apoptosis resistance of blood cells from patients with paroxysmal nocturnal hemoglobinuria, aplastic anemia, and myelodysplastic syndrome. Blood 1997,90:2716-22.
95. Araten DJ, Luzzatto L, Notaro R. Severe telomere shortening in patients with paroxysmal nocturnal hemoglobinuria affects both GPI- and GPI+ hematopoiesis. Blood, 2003, 102(2): 514-6.
96. Dacie JV, Gilpin A: Refractory anaemia (Fanconi type). Arch Dis Child. 1944, 19:155-162,
97. Tumen J, Kline LB, Fay JW, et al. Complement sensitivity of paroxysmal nocturnal hemoglobinuria bone marrow cells. Blood 1980,55:1040-6.
98. Rotoli B, Robledo R, Luzzatto L. Decreased number of circulating BFU-Es in paroxysmal nocturnal hemoglobinuria. Blood 1982,60: 157-9.
99. Nissen C, Tichelli A, et al.: High incidence of transiently appearing complement-sensitive bone marrow precursor cells in patients with severe aplastic anemia-A possible role of high endogenous IL-2 in their suppression. Acta Haematol. 1999,101:165-172.
100. Schrezenmeier H, Hertenstein B, Wagner B, et al. A pathogenetic link between aplastic anemia and paroxysmal nocturnal hemoglobinuria is suggested by a high frequency of aplastic anemia patients with a deficiency of phosphatidylinositol glycan anchored proteins. Exp Hematol 1995;23:81-7.
101. Daniel E.Dunn, Patcharin Tanawattanacharoen, et al. Paroxysmal nocturnal hemoglubinuria cells in patients with bone marrow failure syndromes. Ann Intern Med. 1999,131(6):401-8.
102. Bacigalupo A, Hows J, Gluckrnan E, et al. Bone marrow transplantation (BMT) versus immunosupression for the treatment of severe aplastic anemia (SAA): A report of the EBMT SSA Working Party. Br J Haematol. 1988, 70: 177-182.
103. Balleari E, Gatti AM, Mareni C, et al. Recombinant human erythropoietin for long-term treatment of anemia in paroxysmal nocturnal hemoglobinuria. Haematologica 1996,81:143-147.
104. Mathe G, Amiel J, Schwarzenberg L, et al: Bone marrow graft in man after condidtioningby antilymphocyte globuline. Br Med J 1970,2:131-136.
105. Socie G, Henry-Amar M,et al. Malignant tumors occurring after treatment of aplastic anemia .European Bone Marrow Transplantation—Severe Asplatic Anemia Working Party.N Engl J Med. 1993,329:1153-7.
106. Yong NS. The problem of clonality in aplastic anemia: Dr Dameshek's riddle,restated .Blood. 1992,79:1385-92.
107. Ware RE, Howard TA, Kamitani T, Chang H-M, Yeh TH, Seldin MF. Chromosomal assignment of genes involved in glycosylphosphatidylinositol anchor biosynthesis: implications for the pathogenesis of paroxysmal nocturnal hemogtobinuria.Blood 1994,83:3753-7.
108. Teramura M, Kobayashi S, Iwabe K, et al: Mechanism of action of antithymocyte globulin in the treatment of aplastic anaemia: In vitro evidence for the presence of immunosuppres sive mechanism. Pr J Haematol 1997,96:80-84,
109. Hershko C, Ho WG, Gale RP, Cline MJ. Cure of aplastic anemia in paroxysmal nocturnal hamoglobinuria by marrow transfusion from identical twin: failure of peripheral-leucocyte transfusion to correct marrow aplasia. Lancet 1979,1:945-7.
110. Endo M, Beatty PG, Vreeke TM, Wittwer CT, Singh SP, Parker CJ. Syngeneic bone marrow transplantation without conditioning in a patient with paroxysmal nocturnal hemoglobinuria: in vivo evidence that the mutant stem cells have a survival advantage. Blood 1996,88:742-50
111. Brett SJ, Baxter G, Cooper H, et al. Emergence of CD52-, glycosylphosphatidylinositol-anchor-defic lymphocytes in rheumatoid arthritis patients following Campath-IH treatment. Int Immunol 1995,8:325-34.
112. Taylor VC, Sims M, Brett S, et al: Antibody selection against CD52 produces a paroxysmal nocturnal haemoglobinuria phenotype in human lymphocytes by a novel mechanism. Biochem J. 1997,322:919-925.
113. Rawstron AC, Rollinson SJ, Richards S, et al. GPIdeficient cells (PNH-phenotype) are present in most normal individuals. Blood 90:273a, 1997 (suppl 1)
114. Rawstron AC. Rollinson SJ. Richards S. et al: The PNH phenotype cells that emerge in most patients after CAMPATH-1H therapy are present prior to treatment. Br J Haematol 107:148-153, 1C)'S9
115. Luzzatto L ,Bessler M, et al.: Somatic mutation in paroxysmal nocturnal hemoglobinuria: A blessing in Disguise? Cell. 1997,88(l):l-4.
116. Araten, D. Nafa,K., Pakdeesuwan,K.,and Luzzatto L.PNH cells and GPI-Agene mutations in normal donors.Blood. 1998,92(Suppl.l):471a(Abstr.)
117. Tremml G, Dominguez C, Rostil V, et ai: Increased sensitivity to complement and a decreased red cell life span in mice mosaic for a non-functional Piga gene. Blood. 1999,94(9): 2945-54.
118. Dunn DE, Tanawattanacharoen P, Boccuni P, et al: Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes [see comments]. Ann Intern Med 1999,131:401-408.
119. Metzgar D, Wills C: Evidence for the adaptive evolution of mutation rates. Cell 101:581-584,2000.
120. Foster FL. Adaptive mutation: Implications for evolution. Bioessays2000, 22:1067-1074.121. Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med 1997,336:1365-1372.
122. Sloand EM, Fuhrer M, Keyvanfar K, et al. Cytogenetic abnormalities in paroxysmal nocturnal haemoglobinuria usually occur in haematopoietic cells that are glycosylphosphatidylinositol-anchored protein (GPI-AP) positive. Br J Haematol. 2003,123(1):173-6.
123. Sholar PW, Bell WR. Thrombolytic therapy for inferior vena cava thrombosis in paroxysmal nocturnal hemoglobinuria. Ann Intern Med 1985,103:539-541.
124. Bourantas K, High dose recombinant human erythropoietin and low-dose corticosteroids for treatment of anemia in paroxysmal nocturnal hemoglobinuria. Acta Hematol. 1994,91:62-65.
125. Schaefer A, Jasinski M, Bessler M. High-dose cyclophosphamide does not eradicate paroxysmal nocturnal haemoglobinuria haematopoiesis in mice carrying a Piga gene mutation. Br J Haematol. 2003, 120(5):903-6.
126. Raiola AM, Van Liny MT, Lamparelli T, et al.: Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria Haematol. 2000,85:59-62.
127. Griscelli-Bennaceur A, Gluckman E , Scrobohaci ML, et al.: Aplastic anemia and paroxysmal nocturnal hemoglobinuria: search for a pathogenetic link. Blood 1995,85:1354-1363.
128. Nafa K, Bessler M, Deeg HJ, et al. New somatic mutation in the PIG-A gene emerges at relapse of paroxysmal nocturnal hemoglobinuria. Blood 1998,92:3422-7.
129. Graham MI,, Rosse WE Halperin EC, et al: Resolution of Budd-Chiari syndrome following bone marrow transplantation for paroxysmal nocturnal hemoglobinuria. Br J Haematol 1996,92:707-710.
130. Doukas MA, Fleming D, Jennings D, Identical twin marrow transplantation for venous thrombosis in paroxysmal nocturnal hemoglobinuria: long term complete remission as assessed by flow cytometry. Bone marrow transplant 1998,22:717-721.
131. Mcmullin MF, Hillmen P, Jacson J, et al. Tissue plasminogen activator for hepatic vein thrombosis in paroxysmal nocturnal hemoglobinuria.J Intern Med. 1994: ,235:85-89.
132. Hillmen P, Hall C, Marsh JC, et al., Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. Engl J Med. 2004 Feb 5; 350(6):552-9.
133. Spitzer D, Unsinger J, Bessler M, Atkinson JP. ScFv-mediated in vivo targeting of DAF to erythrocytes inhibits lysis by complement. Mol Immunol. 2004, 40(13): 911-9.1 Boccuni P, Vecchio Del, et al. Glycosyl-phosphatidylinositol(GPI)-anchored molecues and the pathogenesis of paroxysmal nocturnal hemoglobinuria. Crit Rev Oncol Hematol, 2000, 33: 25-43.
2 Frickhofen N, Kaltwasser JP, Schrezenmeier H, et al. Treatment of aplastic anemia with antithymocyte globulin and methylprednisolone with or without cyclosporin. N Engl J Med, 1991, 324: 1297-1304.
3 Rosenfeld SE, Kimball J, Vining D, et al. Intensive immunosuppression with antithymocyte globulin and cyclosporin as treatment for severe acquire aplastic anemia, Blood, 1995, 85: 3058-65.
4 Schubert C, Scholz C. Ggeissler RG, et al. G-CSF and cyclosporin induce an increase of normal cells in paroxysmal nocturnal hemoglobinuria, Ann Hematol, 1997, 74: 225-230.
5 Stoppa AM, Vey N, Sainty D, et al. Correction of aplastic anaemia complicating paroxysmal nocturnal hemoglobinuria: absence of eradication of the PNH clone and dependence of response on cyclosporin A administration. Br J Haematol, 1996, 93: 42-44.
6 Kamp H, Imhoff GW, Wolf JT, et al. The effect of cyclosporin on haematologial parameters in patients with paroxysmal nocturnal hemoglobinuria. Br J Haematol, 1995, 89: 78-82.
7 Packman C H. Pathogenesis and management of paroxysmal nocturnal hemoglobinuria, Blood Reviews, 1998, 12: 1-11.
8 Ronald L. Paquette, Ryan Yoshimura, Charles Vbiseh, et al. Clinical characteristics predict response to antithymocyte globulin in paroxysmal nocturnal hemoglobinuria, Br J Haematol, 1997, 96: 92-97.
9 Schrezenmeier H. Hertenstein B, Wagner B, et al. A pathogenetic link between aplastic anemia and paroxysmal nocturnal hemoglobinuria is suggested by high frequency of aplastic anemia patients with a deficiency of glycosylphosphatidilinositol anchored protein. Exp Hematol, 1995, 23: 81-87
10 Brodsky RA, Sensenbrenner LL, Jones RJ. Complete remission in severe aplastic anemia after high-dose cyclophasphomide without bone marrow transplantation. Blood, 1996, 87: 491-494.
11 Endo M, Beatty PG, Vreeke TM, et al. Syngeneic bone marrow transplantation without conditioning in a patient with paroxysmal nocturnal haemoglobinuria: in vivo evidence that the mutant stem cells have a survival advantage. Blood, 1996, 88: 742-750.
12 邵宗鸿，赵明峰，李克，等低剂量联合化疗对难治性、复发性阵发性睡眠性血红蛋白尿的疗效观察 中国实用内科杂志，2000，20：607-609．
13 Bemba M, Guradiola P, Garderet LU, et al. Bone marrow transplantation for paroxysmal nocturnal haemoglobinuria. Br J Haematol; 1999, 105: 366-368.
14 Suenaga K, Kanda Y, Niiya H, et al. Successful application of nonmyeloablative transplantation for paroxysmal nocturnal hemoglobinuria, Exp Hematol, 2001, 29: 639-642.
15 Raiola AM, van Lint Mr, Lamparelli r. Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria. Haematologica 2000, 85: 59-62,16 Saso R, March J, Cevreska L, et al. Bone marrow transplantation for paroxysmal nocturnal haemoglobinuria. Br J Haematol, 1999, 104:392-396.
17 Woodard P, Wang W, Pitts N, et al. paroxysmal nocturnal hemoglobinuria successful unrelated donor bone marrow transplantation for paroxysmal nocturnal hemoglobinuria,Bone Marrow Transplant,2001, 27:589-592.
18 Champlin RE, Feig SA, Sparkes RS, et al. Bone marrow transplantation from identical twins in the treatment of aplastic anemia: implication for the pathogenesis of the disease. Br J Haematol,1984,56:455-463.
19 Kolb HJ, Holler E, Bender-Gotze C, et al. Myeloablative conditioning for marrow transplantation in myelodysplastic syndromes and paroxysmal nocturnal haemoglobinuria. Bone Marrow Transplant,1989, 4:29-34.
20 Luzzatto L, Bessler M. The duel pathogenesis of paroxysmal nocturnal hemoglobinuria. Curr Opin Hematol 1996,3:101-110.
21 Mikhailova EA, Turbina NS,et al. Cytostatic threapy in paroxysmal nocturnal hemoglobinuria. Probl Gemato Prereliv Krovi.1979, 24(8):38-41.