Function and malfunction of hematopoietic stem cells in primary bone marrow failure syndromes

Current Stem Cell Research and Therapy

Volumn 2, Issue 1, 2007, Pages 39-52

  Risitano, Antonio M ^a   Maciejewski, Jaroslaw P ^b   Selleri, Carmine ^a   Rotoli, Bruno ^a  

^a UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^b TAUSSIG CANCER INSTITUTE   (United States)

Author keywords

Aplastic anemia; Bone marrow failure; Dyskeratosis congenita; Fanconi's anemia; Hematopoietic stem cells; Paroxysmal nocturnal hemoglobinuria

Indexed keywords

ALEMTUZUMAB; ALLOPURINOL; ANTIBIOTIC AGENT; ANTICONVULSIVE AGENT; ANTIDIABETIC AGENT; ANTIPROTOZOAL AGENT; ANTITHYROID AGENT; CARBONATE DEHYDRATASE INHIBITOR; CHLORAMPHENICOL; GLYCAN; GOLD DERIVATIVE; NONSTEROID ANTIINFLAMMATORY AGENT; PHOSPHATIDYLINOSITOL; SEDATIVE AGENT; SULFONAMIDE; TRANQUILIZER;

APLASTIC ANEMIA; AUTOIMMUNE DISEASE; BONE MARROW; BONE MARROW APLASIA; BONE MARROW DEPRESSION; BONE MARROW TOXICITY; CANCER; CELL FUNCTION; CELLULAR IMMUNITY; CLINICAL FEATURE; CLONAL VARIATION; DEPLETION; DRUG WITHDRAWAL; GENE MUTATION; GENETIC POLYMORPHISM; GENETIC SUSCEPTIBILITY; GERM LINE; HEMATOLOGIC DISEASE; HEMATOPOIESIS; HEMATOPOIETIC STEM CELL; HETEROZYGOTE; HUMAN; IMMUNE SYSTEM; LYMPHATIC LEUKEMIA; LYMPHOCYTE PROLIFERATION; LYMPHOMA; LYMPHOPROLIFERATIVE DISEASE; MOLECULAR INTERACTION; NONHUMAN; PANCYTOPENIA; PAROXYSMAL NOCTURNAL HEMOGLOBINURIA; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; PROGENY; RADIATION INJURY; REVIEW; SOMATIC MUTATION; VIRUS;

ANEMIA, APLASTIC; ANIMALS; BONE MARROW DISEASES; HEMATOPOIETIC STEM CELLS; HEMOGLOBINURIA, PAROXYSMAL; HUMANS; LEUKEMIA, LARGE GRANULAR LYMPHOCYTIC; SYNDROME;

EID: 34248593553     PISSN: 1574888X     EISSN: None     Source Type: Journal    
DOI: 10.2174/157488807779316982     Document Type: Review

References (146)

1. Tavassoli MV. Bone marrow: the seedbed of blood. In: Wintrobe MM, ed. Blood, pure and eloquent: a story of discovery, of people, and of ideas. New York, McGraw-Hill; 1980: 57-79.
2. Lajitha LG. The common ancestral cell. In: Wintrobe MM, ed. Blood, pure and eloquent: a story of discovery, of people, and of ideas. New York, McGraw-Hill; 1980: 80-95.
3. Gordon MY. Physiology and function of the haemopoietic microenvironment. Br J Haematol. 1994; 86: 241-3.
4. Ogawa M, Porter PN, Nakahata T. Renewal and commitment to differentiation of hemopoietic stem cells (an interpretive review). Blood 1983; 61: 823-9.
5. Kondo M, Wagers AJ, Manz MG, et al. Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu Rev Immunol 2003; 21: 759-806.
6. Young NS. Acquired aplastic anemia. In: Young NS, ed. Bone marrow failure syndromes. Philadelphia, W.B. Saunders; 2000: 1-46.
7. Alter BP, Young N. The bone marrow failure syndromes. In: DG Nathan, SH Oski, eds. Nathan and Oski's hematology of infants and childhood, 5th ed. Philadelphia, WB Saunders; 1998: 237-335.
8. Butturini A, Gale RP, Verlander PC, Adler-Brecher B, Gillio AP, Auerbach AD. Hematologic abnormalities in Fanconi anemia: an International Fanconi Anemia Registry study. Blood 1995; 85: 1148-9.
9. Bagnara GP, Strippoli P, Bonsi L, et al. Effect of stem cell factor on colony growth from acquired and constitutional (Fanconi) aplastic anemia. Blood 1992; 80: 382-7.
10. Stark R, Thierry D, Richard P, Gluckman E. Long-term bone marrow culture in Fanconi's anaemia. Br J Haematol 1993; 83: 554-9.
11. D'Andrea AD, Grompe M. The Fanconi anaemia/BRCA pathway. Nat Rev Cancer 2003; 3: 23-34.
12. Joenje H, Patel KJ. The emerging genetic and molecular basis of Fanconi anaemia. Nat Rev Genet 2001; 2: 446-57.
13. Ruppitsch W, Meisslitzer C, Weirich-Schwaiger H, et al. The role of oxygen metabolism for the pathological phenotype of Fanconi anemia. Hum Genet 1997; 99: 710-719.
14. Aube M, Lafrance M, Brodeur I, Delisle MC, Carreau M. Fanconi anemia genes are highly expressed in primitive CD34+ hematopoietic cells. BMC Blood Disord 2003; 3: 1.
15. Zhang X, Li J, Sejas DP, Pang Q. Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cells. Blood 2005; 106: 75-85.
16. Habi O, Delisle MC, Messier N, Carreau M. Lack of self-renewal capacity in Fancc-/- stem cells after ex vivo expansion. Stem Cells 2005; 23: 1135-41.
17. Dokal I. Dyskeratosis congenita in all its forms. Br J Hematol 2000; 109: 121-129.
18. Marsh JC, Will AJ, Hows JM, et al. "Stem cell" origin of the hematopoietic defect in dyskeratosis congenita. Blood 1992; 79: 3138-44.
19. Vulliamy TJ, Knight SW, Mason PJ, Dokal I. Very short telomeres in the peripheral blood of patients with X-linked and autosomal dyskeratosis congenita. Blood Cells Mol Dis 2001; 27: 353-7.
20. Heiss NS, Knight SW, Vulliamy TJ, et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 1998; 19: 32-8.
21. Mitchell JR, Wood E, Collins K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature 1999; 402: 551-5.
22. Mochizuki Y, He J, Kulkarni S, Bessler M, Mason PJ. Mouse dyskerin mutations affect accumulation of telomerase RNA and small nucleolar RNA, telomerase activity, and ribosomal RNA processing. Proc Natl Acad Sci U S A 2004; 101: 10756-61.
23. Vulliamy T, Marrone A, Goldman F, et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 2001; 413: 432-5.
24. Ly H, Schertzer M, Jastaniab W, et al. Identification and functional characterization of 2 variant alleles of the telomerase RNA template gene (TERC) in a patient with dyskeratosis congenita. Blood 2005; 106: 1246-52.
25. Fogarty PF, Yamaguchi H, Wiestner A, et al. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet 2003; 362: 1628-30.
26. Greenwood MJ, Lansdorp PM. Telomeres, telomerase, and hematopoietic stem cell biology. Arch Med Res 2003; 34: 489-95.
27. Dror Y, Freedman MH. Shwachman-Diamond syndrome marrow cells show abnormally increased apoptosis mediated through the Fas pathway. Blood 2001; 97: 3011-6.
28. Dror Y, Freedman MH. Shwachman-Diamond syndrome: An inherited preleukemic bone marrow failure disorder with aberrant hematopoietic progenitors and faulty marrow microenvironment. Blood 1999; 94 3048-54.
29. Kuijpers TW, Alders M, Tool AT, Mellink C, Roos D, Hennekam RC. Hematologic abnormalities in Shwachman Diamond syndrome: lack of genotype-phenotype relationship. Blood 2005; 106: 356-61.
30. Boocock GR, Morrison JA, Popovic M, et al. Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet 2003; 33:97-101.
31. Savchenko A, Krogan N, Cort JR, et al. The Shwachman-Bodian-Diamond syndrome protein family is involved in RNA metabolism. J Biol Chem 2005; 280: 19213-20.
32. Boocock GR, Marit MR, Rommens JM. Phylogeny, sequence conservation, and functional complementation of the SBDS protein family. Genomics 2006; [Epub ahead of print]
33. Liu JM, Ellis SR. Ribosomes and marrow failure: coincidental association or molecular paradigm? Blood 2006; 107: 4583-88.
34. Muraoka K, Ishii E, Tsuji K, et al. Defective response to thrombopoietin and impaired expression of c-mpl mRNA of bone marrow cells in congenital amegakaryocytic thrombocytopenia. Br J Haematol 1997; 96: 287-92.
35. van den Oudenrijn S, Bruin M, Folman CC, et al. Mutations in the thrombopoietin receptor, Mp1, in children with congenital amegakaryocytic thrombocytopenia. Br J Haematol 2000; 110: 441-8.
36. Ballmaier M, Germeshausen M, Schulze H, et al. c-mp1 mutations are the cause of congenital amegakaryocytic thrombocytopenia. Blood 2001; 97: 139-46.
37. Zeidler C, Welte K. Kostmann syndrome and severe congenital neutropenia. Semin Hematol 2002; 39: 82-8.
38. Dale DC, Person RE, Bolyard AA, et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 2000; 96: 2317-22.
39. Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet 1999; 23: 433-6.
40. Vlachos A, Klein GW, Lipton JM. The Diamond Blackfan Anemia Registry: tool for investigating the epidemiology and biology of Diamond-Blackfan anemia. J Pediatr Hematol Oncol 2001; 23: 377-82.
41. Nathan DG, Clarke BJ, Hillman DG, Alter BP, Housman DE. Erythroid precursors in congenital hypoplastic (Diamond-Blackfan) anemia. J Clin Invest 1978; 61: 489-98.
42. Lipton JM, Kudisch M, Gross R, Nathan DG. Defective erythroid progenitor differentiation system in congenital hypoplastic (Diamond-Blackfan) anemia. Blood 1986; 67: 962-8.
43. Gustavsson P, Willing TN, van Haeringen A, et al. Diamond-Blackfan anaemia: genetic homogeneity for a gene on chromosome 19q13 restricted to 1.8 Mb. Nat Genet 1997; 16: 368-71.
44. Gazda H, Lipton JM, Willig TN, et al. Evidence for linkage of familial Diamond-Blackfan anemia to chromosome 8p23.3-p22 and for non-19q non-8p disease. Blood 2001; 97: 2145-50.
45. Quigley JG, Gazda H, Yang Z, Ball S, Sieff CA, Abkowitz JL. Investigation of a putative role for FLVCR, a cytoplasmic heme exporter, in Diamond-Blackfan anemia. Blood Cells Mol Dis 2005; 35: 189-92.
46. Draptchinskaia N, Gustavsson P, Andersson B, et al. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet 1999; 21: 169-75.
47. Makitie O, Kaitila I. Cartilage-hair hypoplasia - clinical manifestations in 108 Finnish patients. Eur J Pediatr 1993; 152: 211-7.
48. Williams MS, Ettinger RS, Hermanns P, et al. The natural history of severe anemia in cartilage-hair hypoplasia. Am J Med Genet A 2005; 138: 35-40.
49. Ridanpaa M, van Eenennaam H, Pelin K, et al. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell 2001; 104: 195-203.
50. Brown KE, Tisdale J, Barrett AJ, Dunbar CE, Young NS. Hepatitis-associated aplastic anemia. N Engl J Med 1997; 336: 1059-1064.
51. Ohara A, Kojima, S, Okamura J, et al. Evolution of myelodysplastic syndrome and acute myelogenous leukaemia in children with hepatitis-associated aplastic anaemia. Br J Haematol 2002; 116: 151-154.
52. Baranski B, Armstrong G, Truman JT, Quinnan GV Jr., Straus SE, Young NS. Epstein-Barr virus in the bone marrow of patients with aplastic anemia. Ann Intern Med 1998; 109: 695-704.
53. Manz CY, Nissen C, Wodnar-Filipowicz A. Deficiency of CD34+ c-kit+ and CD34+38- hematopoietic precursors in aplastic anemia after immunosuppressive treatment. Am J Hematol 1996; 52: 264-274.
54. Maciejewski JP, Anderson S, Katevas P, Young NS. Phenotypic and functional analysis of bone marrow progenitor cell compartment in bone marrow failure. Br J Haematol 1994; 87: 227-234.
55. Maciejewski JP, Selleri C, Sato T, Anderson S, Young NS. A severe and consistent deficit in marrow and circulating primitive hematopoietic cells (long-term culture-initiating cells) in acquired aplastic anemia. Blood 1996; 88: 1983-1991.
56. Bacigalupo A, Piaggio G, Podesta M, et al. Collection of peripheral blood hematopoietic progenitors (PBHP) from patients with severe aplastic anemia (SAA) after prolonged administration of granulocyte colony-stimulating factor. Blood 1993; 82: 1410-1414.
57. Scopes J, Bagnara M, Gordon-Smith EC, Ball SE, Gibson FM. Haemopoietic progenitor cells are reduced in aplastic anaemia. Br J Haematol 1994; 86: 427-430.
58. Scopes J, Daly S, Atkinson R, Ball SE, Gordon-Smith EC, Gibson FM. Aplastic anemia: evidence for dysfunctional bone marrow progenitor cells and the corrective effect of granulocyte colony-stimulating factor in vitro. Blood 1996; 87: 3179-85.
59. Maciejewski JP, Kim S, Sloand E, Selleri C, Young NS. Sustained long-term hematologic recovery despite a marked quantitative defect in the stem cell compartment of patients with aplastic anemia after immunosuppressive therapy. Am J Hematol 2000; 65: 123-131.
60. Schrezenmeier H, Jenal M, Herrmann F, Heimpel H, Raghavachar A. Quantitative analysis of cobblestone area-forming cells in bone marrow of patients with aplastic anemia by limiting dilution assay. Blood 1996; 88: 4474-4480.
61. Sutherland HJ, Eaves CJ, Eaves AC, Dragowska W, Lansdorp PM. Characterization and partial purification of human marrow cells capable of initiating long-term hematopoiesis in vitro. Blood 1989; 74: 1563-1570.
62. Pettengell R, Luft T, Henschler R, et al. Direct comparison by limiting dilution analysis of long-term culture-initiating cells in human bone marrow, umbilical cord blood, and blood stem cells. Blood 1994; 84: 3653-3659.
63. Podesta M, Piaggio G, Frassoni F, et al. The assessment of the hematopoietic reservoir after immunosuppressive therapy or bone marrow transplantation in severe aplastic anemia. Blood 1998; 91: 1959-1965.
64. Rizzo S, Scopes J, Elebute MO, Papadaki HA, Gordon-Smith EC, Gibson FM. Stem cell defect in aplastic anemia: reduced long term culture-initiating cells (LTC-IC) in CD34+ cells isolated from aplastic anemia patient bone marrow. Hematol J 2002; 3: 230-236.
65. Rizzo S, Scopes J, Draycott GS, et al. Quiescent (5-fluorouracil-resistant) aplastic anemia hematopoietic cells in vitro. Exp Hematol 2004; 32: 665-72.
66. Marsh JC, Chang J, Testa NG, Hows JM, Dexter TM. In vitro assessment of marrow 'stem cell' and stromal cell function in aplastic anaemia. Br J Haematol 1991; 78: 258-267.
67. Novitzky N, Jacobs P. Immunosuppressive therapy in bone marrow aplasia: the stroma functions normally to support hematopoiesis. Exp Hematol 1995; 23:1472-1477.
68. Novitzky N, Jacobs P. Marrow stem cell and stroma cell function in aplastic anaemia. Br J Haematol 1991; 79: 531-533.
69. Bacigalupo A, Valle M, Podesta M, et al. T-cell suppression mediated by mesenchymal stem cells is deficient in patients with severe aplastic anemia. Exp Hematol 2005; 33: 819-27.
70. Philpott NJ, Scopes J, Marsh JC, Gordon-Smith EC, Gibson FM. Increased apoptosis in aplastic anemia bone marrow progenitor cells: possible pathophysiologic significance. Exp Hematol 1995; 23: 1642-1648.
71. Killick SB, Cox CV, Marsh JC, Gordon-Smith EC, Gibson FM. Mechanisms of bone marrow progenitor cell apoptosis in aplastic anaemia and the effect of anti-thymocyte globulin: examination of the role of the Fas-Fas-L interaction. Br J Haematol 2000; 111: 1164-1169.
72. Ismail M, Gibson FM, Gordon-Smith EC, Rutherford TR. Bcl-2 and Bcl-x expression in the CD34+ cells of aplastic anaemia patients: relationship with increased apoptosis and upregulation of Fas antigen. Br J Haematol 2001; 113: 706-712.
73. Young N, Maciejewski JP. Aplastic Anemia. In: Hoffman R, Benz EJJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P, ed. Hematology (Basic Principles and Practice). Philadelphia, Churchill Livingstone; 2000: 297-330.
74. Young NS. Acquired aplastic anemia. Ann Intern Med 2002; 136: 534-546.
75. Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med 1997; 336: 1365-1372.
76. Dufour C, Corcione A, Svahn J, Haupt R, Battilana N, Pistoia V. Interferon gamma and tumour necrosis factor alpha are overexpressed in bone marrow T lymphocytes from paediatric patients with aplastic anaemia. Br J Haematol 2001; 115: 1023-1031.
77. Sloand E, Maciejewski JP, Tisdale J, Follman D, Young NS. Intracellular Interferon-γ (IFN-γ) in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia. Blood 2002; 100: 3129-3135.
78. Sato T, Selleri C, Anderson S, Young NS, Maciejewski JP. Expression and modulation of cellular receptors for interferon-gamma, tumour necrosis factor, and Fas on human bone marrow CD34+ cells. Br J Haematol 1997; 97: 356-365.
79. Maciejewski JP, Selleri C, Sato T, Anderson S, Young T. Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anaemia. Br J Haematol 1995; 91: 245-252.
80. Maciejewski J, Selleri C, Anderson S, Young NS. Fas antigen expression on CD34+ human marrow cells is induced by interferon gamma and tumor necrosis factor alpha and potentiates cytokine-mediated hematopoietic suppression in vitro. Blood 1995; 85: 3183-3190.
81. Selleri C, Maciejewski JP, Sato T, Young NS. Interferon-gamma constitutively expressed in the stromal microenvironment of human marrow cultures mediates potent hematopoietic inhibition. Blood 1996; 87: 4149-4157.
82. Marsh JC. Hematopoietic growth factors in the pathogenesis and for the treatment of aplastic anemia. Semin Hematol 2000; 37: 81-90.
83. Callera F, Falcao RP. Increased apoptotic cells in bone marrow biopsies from patients with aplastic anaemia. Br J Haematol 1997; 98: 18-20.
84. Nistico A, Young NS. gamma-Interferon gene expression in the bone marrow of patients with aplastic anemia. Ann Intern Med 1994; 120: 463-469.
85. Marsh JC, Gibson FM, Prue RL, et al. Serum thrombopoietin levels in patients with aplastic anaemia. Br J Haematol 1996; 95: 605-610.
86. Dybedal I, Yang L, Bryder D, Aastrand-Grundstrom I, Leandersson K, Jacobsen SE. Human reconstituting hematopoietic stem cells up-regulate Fas expression upon active cell cycling but remain resistant to Fas-induced suppression. Blood 2003; 102: 118-126.
87. Maciejewski JP, Selleri C, Sato T, et al. Nitric oxide suppression of human hematopoiesis in vitro. Contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha. J Clin Invest 1995; 96: 1085-1092.
88. Selleri C, Sato T, Raiola AM, Rotoli B, Young NS, Maciejewski JP. Induction of nitric oxide synthase is involved in the mechanism of Fas-mediated apoptosis in haemopoietic cells. Br J Haematol 1997; 99: 481-489.
89. Zeng W, Chen G, Kajigaya S, et al. Gene expression profiling in CD34 cells to identify differences between aplastic anemia patients and healthy volunteers. Blood 2004; 103: 325-332.
90. Nakao S, Takami A, Takamatsu H, et al. Isolation of a T-cell clone showing HLA-DRB1*0405-restricted cytotoxicity for hematopoietic cells in a patient with aplastic anemia. Blood 1997; 89: 3691-3699.
91. Zoumbos N, Gascon P, Trost S, Djeu J, Young N. Circulating activated suppressor T lymphocytes in aplastic anemia. N Engl J Med 1985; 312: 257-265.
92. Zeng W, Nakao S, Takamatsu H, et al. Characterization of T-cell repertoire of the bone marrow in immune-mediated aplastic anemia: evidence for the involvement of antigen-driven T-cell response in cyclosporine-dependent aplastic anemia. Blood 1999; 93: 3008-16.
93. Kook H, Risitano AM, Zeng W, et al. Changes in T-cell receptor VB repertoire in aplastic anemia: effects of different immunosuppressive regimens. Blood 2002; 99: 3668-3675.
94. Risitano AM, Kook H, Zeng W, Chen G, Young NS, Maciejewski JP. Oligoclonal and polyclonal CD4 and CD8 lymphocytes in aplastic anemia and paroxysmal nocturnal hemoglobinuria measured by Vβ CDR3 spectratyping and flow cytometry. Blood 2002; 100: 178-183.
95. Plasilova M, Risitano A, Maciejewski JP. Application of the molecular analysis of the T-cell receptor repertoire in the study of immune-mediated hematologic diseases. Hematology 2003; 8: 173-181.
96. Zeng W, Maciejewski JP, Chen G, Young NS. Limited heterogeneity of T-cell receptor VB usage in aplastic anemia. J Clin Invest 2001; 108: 765-773.
97. Risitano AM, Maciejewski JP, Green S, Plasilova M, Zeng W, Young NS. In vivo dominant immune responses in aplastic anemia patients: molecular tracking of putatively pathogenic T cells by TCRβ-CDR3 sequencing. Lancet 2004; 364: 353-363.
98. Brummendorf TH, Dragowska W, Lansdorp PM. Asymmetric cell divisions in hematopoietic stem cells. Ann N Y Acad Sci 1999; 872: 265-272.
99. Brummendorf TH, Rufer N, Holyoake TL, et al. Telomere length dynamics in normal individuals and in patients with hematopoietic stem cell-associated disorders. Ann N Y Acad Sci 2001; 938: 293-303.
100. Brummendorf TH, Maciejewski JP, Mak J, Young NS, Lansdorp PM. Telomere length in leukocyte subpopulations of patients with aplastic anemia. Blood 2001; 97: 895-900.
101. Chiu CP, Dragowska W, Kim NW, et al. Differential expression of telomerase activity in hematopoietic progenitors from adult human bone marrow. Stem Cells 1996; 14: 239-248.
102. Ball SE, Gibson FM, Rizzo S, Tooze JA, Marsh JC, Gordon-Smith EC. Progressive telomere shortening in aplastic anemia. Blood 1998; 91: 3582-3592.
103. Lee JJ, Kock H, Chung IJ, et al. Telomere length changes in patients with aplastic anaemia. Br J Haematol 2001; 112: 1025-1030.
104. Yamaguchi H, Baerlocher GM, Lansdorp PM, et al. Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome. Blood 2003; 102: 908-1916.
105. Vulliamy T, Marrone A, Dokal I, Mason PJ. Association between aplastic anaemia and mutations in telomerase RNA. Lancet 2002; 359: 2168-2170.
106. Ly H, Calado RT, Allard P, et al. Functional characterization of telomerase RNA variants found in patients with hematologic disorders. Blood 2005; 105: 2332-9.
107. Yamaguchi H, Calado RT, Ly H, et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med 2005; 352: 1413-24.
108. Maciejewski JP, Risitano A, Sloand EM, Nunez O, Young NS. Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood 2002; 99: 3129-3135.
109. Maciejewski JP, Selleri C. Evolution of clonal cytogenetic abnormalities in aplastic anemia. Leuk Lymphoma 2004; 45: 433-40.
110. Kojima S, Ohara A, Tsuchida M, et al. Group Risk factors for evolution of acquired aplastic anemia into myelodysplastic syndrome and acute myeloid leukemia after immunosuppressive therapy in children. Blood 2002; 100; 786-90.
111. Bacigalupo A, Bruno B, Saracco P, et al. Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients. Blood 2000; 95:1931-1934.
112. Lamy T, Loughran TP Jr. Clinical features of large granular lymphocytic leukemia. Semin Hematol 2003; 40: 185-195.
113. Kanchan K, Loughran TP Jr. Antigen-driven clonal T cell expansion in disorders of hematopoiesis. Leuk Res 2003; 27: 291-292.
114. Akashi K, Shibuya T, Taniguchi S, et al. Multiple autoimmune haemopoietic disorders and insidious clonal proliferation of large granular lymphocytes. Br J Haematol 1999; 107: 670-3.
115. Bowman SJ, Bhavnani M, Geddes GC, et al. Large granular lymphocyte expansions in patients with Felty's syndrome: analysis using anti-T cell receptor V beta-specific monoclonal antibodies. Clin Exp Immunol 1995; 101: 18-24.
116. Liu JH, Wei S, Lamy T, et al. Blockade of Fas-dependent apoptosis by soluble Fas in LGL leukemia. Blood 2002;100: 1449-53.
117. O'Keefe CL, Plasilova M, Wlodarski M, et al. Molecular analysis of TCR clonotypes in LGL: a clonal model for polyclonal responses. J Immunol 2004; 172: 1960-9.
118. Wlodarski MW, O'Keefe C, Howe EC, et al. Pathologic clonal cytotoxic T-cell responses: nonrandom nature of the T-cell-receptor restriction in large granular lymphocyte leukemia. Blood 2005; 106: 2769-80.
119. Young NS, Maciejewski JP. Genetic and environmental effects in paroxysmal nocturnal hemoglobinuria: this little PIG-A goes "Why? Why? Why?". J Clin Invest 2000; 106: 637-641.
120. Luzzatto L, Bessler M, Rotoli B. Somatic mutations in paroxysmal nocturnal hemoglobinuria: a blessing in disguise. Cell 1997; 88: 1-4.
121. Takeda J, Miyata T, Kawagoe K, et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell 1993; 73: 703-11.
122. Nishimura Ji J, Hirota T, Kanakura Y, et al. Long-term support of hematopoiesis by a single stem cell clone in patients with paroxysmal nocturnal hemoglobinuria. Blood 2002; 99: 2748-2751.
123. Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995; 333: 1253-1258.
124. Araten DJ, Nafa K, Pakdeesuwan K, Luzzatto L. Clonal populations of hematopoietic cells with paroxysmal nocturnal hemoglobinuria genotype and phenotype are present in normal individuals. Proc Natl Acad Sci U S A 1999; 96: 5209-5214.
125. Hu R, Mukhina GL, Piantadosi S, Barber JP, Jones RJ, Brodsky RA. PIG-A mutations in normal hematopoiesis. Blood 2005; 105: 3848-54.
126. Hertenstein B, Wagner B, Bunjes D, et al. Emergence of CD52-, phosphatidylinositolglycan-anchor-deficient T lymphocytes after in vivo application of Campath-1H for refractory B-cell non-Hodgkin lymphoma. Blood 1995; 86: 1487-1492.
127. Rosti V, Tremml G, Soares V, Pandolfi PP, Luzzatto L, Bessler M. Murine embryonic stem cells without pig-a gene activity are competent for hematopoiesis with the PNH phenotype but not for clonal expansion. J Clin Invest 1997; 100: 1028-1036.
128. Keller P, Payne JL, Tremml G, et al. FES-Cre targets phosphatidylinositol glycan class A (PIGA) inactivation to hematopoietic stem cells in the bone marrow. J Exp Med 2001; 194: 581-589.
129. Jasinski M, Keller P, Fujiwara Y, Orkin SH, Bessler M. GATA1-Cre mediates Piga gene inactivation in the erythroid/megakaryocytic lineage and leads to circulating red cells with a partial deficiency in glycosyl phosphatidylinositol-linked proteins (paroxysmal nocturnal hemoglobinuria type II cells). Blood 2001; 98: 2248-2255.
130. Maciejewski JP, Sloand EM, Sato T, Anderson S, Young NS. Impaired hematopoiesis in paroxysmal nocturnal hemoglobinuria/aplastic anemia is not associated with a selective proliferative defect in the glycosylphosphatidylinositol-anchored protein-deficient clone. Blood 1997; 89: 1173-81.
131. Rosse WF, Dacie JV. Immune lysis of normal human and paroxysmal nocturnal hemoglobinuria (PNH) red blood cells. I. The sensitivity of PNH red cells to lysis by complement and specific antibody. J Clin Invest 1966;45:736-748.
132. Rotoli B, Robledo R, Scarpato N, Luzzatto L. Two populations of erythroid cell progenitors in paroxysmal nocturnal hemoglobinuria. Blood 1984; 64: 847-851.
133. van der Schoot CE, Huizinga TW, van 't Veer-Korthof ET, Wijmans 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: 1853-1859.
134. Endo M, Ware RE, Vreeke TM, et al. Molecular basis of the heterogeneity of expression of glycosyl phosphatidylinositol anchored proteins in paroxysmal nocturnal hemoglobinuria. Blood 1996; 87: 2546-57.
135. Rotoli B, Luzzatto L. Paroxysmal nocturnal haemoglobinuria. Baillieres Clin Haematol 1989; 2: 113-138.
136. Dunn DE, Liu JM, Young NS. Paroxysmal nocturnal hemoglobinuria. In: Young NS, ed. Bone marrow failure syndromes. Philadelphia, W.B. Saunders; 2000: 99-121.
137. Karadimitris A, Manavalan JS, Thaler HT, et al. Abnormal T-cell repertoire is consistent with immune process underlying the pathogenesis of paroxysmal nocturnal hemoglobinuria. Blood 2000; 96: 2613-262
138. Plasilova M, Risitano AM, O'Keefe CL, Rodriguez A, Wlodarski M, Maciejewski JP. Shared and individual specificities of immunodominant cytotoxic T cell clones in Paroxysmal Nocturnal Hemoglobinuria as determined by molecular analysis. Exp Hematol 2004; 32: 261-269.
139. Karadimitris A, Li K, Notaro R, et al. Association of clonal T-cell large granular lymphocyte disease and paroxysmal nocturnal haemoglobinuria (PNH): further evidence for a pathogenetic link between T cells, aplastic anaemia and PNH. Br J Haematol 2001; 115: 1010-1014.
140. Risitano AM, Maciejewski JP, Muranski P, et al. Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients. Leukemia 2005; 19: 217-22.
141. Poggi A, Negrini S, Zocchi MR, et al. Patients with paroxysmal nocturnal hemoglobinuria have a high frequency of peripheral-blood T cells expressing activating isoforms of inhibiting superfamily receptors. Blood 2005; 106: 2399-408.
142. Chen G, Zeng W, Maciejewski JP, Kcyvanfar K, Billings EM, Young NS. Differential gene expression in hematopoietic progenitors from paroxysmal nocturnal hemoglobinuria patients reveals an apoptosis/immune response in 'normal' phenotype cells. Leukemia 2005; 19: 862-8.
143. Chen R, Nagarajan S, Prince GM, et al. Impaired growth and elevated fas receptor expression in PIGA(+) stem cells in primary paroxysmal nocturnal hemoglobinuria. J Clin Invest. 2000; 106: 689-96.
144. Nagakura S, Ishihara S, Dunn DE, et al. Decreased susceptibility of leukemic cells with PIG-A mutation to natural killer cells in vitro. Blood 2002; 100: 1031-1037.
145. Murakami Y, Kosaka H, Maeda Y, et al. Inefficient response of T lymphocytes to glycosylphosphatidylinositol anchor-negative cells: implications for paroxysmal nocturnal hemoglobinuria. Blood 2002; 100: 4116-4122.
146. Nachbur U, Kassahn D, Yousefi S, Legler DF, Brunner T. Posttranscriptional regulation of Fas (CD95) ligand killing activity by lipid rafts. Blood 2006; 107: 2790-6.