The myelodysplastic syndromes: A matter of life or death

Acta Haematologica

Volumn 111, Issue 1-2, 2004, Pages 78-99

  Parker, Jane E ^a   Mufti, Ghulam J ^b  

^a NORFOLK AND NORWICH UNIVERSITY HOSPITAL   (United Kingdom)

^b KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Acute myeloid leukemia; Apoptosis; Bcl 2; Fas; Mitochondria; Myelodysplastic syndrome; Proliferation; Tumor necrosis factor

Indexed keywords

2,4 DIMETHYL 5 (2 OXO 1H INDOL 3 YLMETHYLENE) 3 PYRROLEPROPIONIC ACID; 5 AZA 2' DEOXYCYTIDINE; AG 13736; AMIFOSTINE; ANGIOGENESIS INHIBITOR; ARSENIC TRIOXIDE; BEVACIZUMAB; BONGKREKIC ACID; CASPASE INHIBITOR; CIPROFLOXACIN; CYCLOSPORIN A; DEXAMETHASONE; DNA METHYLTRANSFERASE; DNA METHYLTRANSFERASE INHIBITOR; ENZYME INHIBITOR; ERYTHROPOIETIN; ETANERCEPT; GRANULOCYTE COLONY STIMULATING FACTOR; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR RECEPTOR; MATRIX METALLOPROTEINASE INHIBITOR; PENTOXIFYLLINE; PRINOMASTAT; PROTEIN FARNESYLTRANSFERASE INHIBITOR; PROTEIN TYROSINE KINASE INHIBITOR; REVEMID; SEMAXANIB; THALIDOMIDE; THYMOCYTE ANTIBODY; UNCLASSIFIED DRUG; VATALANIB;

APOPTOSIS; BONE MARROW; CELL CYCLE; CELL PROLIFERATION; CLINICAL TRIAL; DISEASE COURSE; DNA REPAIR; HEMATOPOIETIC CELL; HUMAN; IMMUNE SYSTEM; IMMUNOSUPPRESSIVE TREATMENT; MEMBRANE PERMEABILITY; MICROENVIRONMENT; MITOCHONDRIAL MEMBRANE; MYELODYSPLASTIC SYNDROME; NONHUMAN; PATHOGENESIS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROGNOSIS; PROTEIN FAMILY; REVIEW; SIGNAL TRANSDUCTION; UPREGULATION;

APOPTOSIS; BONE MARROW CELLS; HUMANS; MYELODYSPLASTIC SYNDROMES;

EID: 0345491535     PISSN: 00015792     EISSN: None     Source Type: Journal    
DOI: 10.1159/000074488     Document Type: Review

References (225)

1. Yoshida Y: Hypothesis: Apoptosis may be the mechanism responsible for the premature intramedullary cell death in the myelodysplastic syndrome. Leukemia 1993;7:144-146.
2. Rajapaksa R, Ginzton N, Rott LS, Greenberg PL: Altered oncoprotein expression and apoptosis in myelodysplastic syndrome marrow cells. Blood 1996;88:4275-4287.
3. Parker JE, Fishlock KL, Czepulkowski B, Pagliuca A, Mufti GJ: The role of apoptosis, proliferation and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukaemia secondary to MDS. Blood 2000;96:3932-3938.
4. Kerr JF, Wyllie AH, Currie AR: Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239-257.
5. Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM: Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 1992;148:2207-2216.
6. Thornberry NA, Lazebnik Y: Caspases: Enemies within. Science 1998;281:12.
7. Nagata S, Golstein P: The Fas death factor. Science 1995;267:1449-1456.
8. Banner DW, D'Arcy A, Janes W, Gentz R, Schoenfeld HJ, Broger C, Loetscher H, Lesslauer W: Crystal structure of the soluble human 55 kD TNF receptor-human TNF β complex: Implications for TNF receptor activation. Cell 1993;73:431-435.
9. Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM: FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 1995;81:505-512.
10. Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME: Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex with the receptor. EMBO J 1995;14:5579-5588.
11. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X: Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 1998;94:481-490.
12. Gross A, Yin XM, Wang K, Wei MC, Jockel J, Milliman C, Erdjument-Bromage H, Tempst P, Korsmeyer SJ: Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J Biol Chem 1999;274:1156-1163.
13. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME: Two CD95 (APO-1/Fas) signaling pathways. EMBO J 1998;17:1675-1687.
14. Marchetti P, Castedo M, Susin SA, Zamzami N, Hirsch T, Macho A, Haeffner A, Hirsch F, Geuskens M, Kroemer G: Mitochondrial permeability transition is a central coordinating event of apoptosis. J Exp Med 1996;184:1155-1160.
15. Skulachev VP: Why are mitochondria involved in apoptosis? Permeability transition pores and apoptosis as selective mechanisms to eliminate superoxide-producing mitochondria and cell. FEBS Lett 1996;397:7-10.
16. Liu X, Kim CN, Yang J, Jemmerson R, Wang X: Induction of apoptotic program in cell-free extracts: Requirement for dATP and cytochrome c. Cell 1996;86:147-157.
17. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X: Cytochome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997;91:479-489.
18. Zou H, Henzel WJ, Liu XS, Lutschg A, Wang XD: Apaf-1, a human protein homologous to C-elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 1997;90:405-413.
19. Pan G, Humke EW, Dixit VM: Activation of caspases triggered by cytochrome c in vitro. FEBS Lett 1998;426:151-154.
20. Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL: Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 2000;102:43-53.
21. Ravagnan L, Roumier T, Kroemer G: Mitochondria, the killer organelles and their weapons. J Cell Physiol 2002;192:131-137.
22. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G: Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999;397:441-446.
23. Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CY, Sasaki T, Elia AJ, Cheng HY, Ravagnan L, Ferri KF, Zamzami N, Wakeham A, Hakem R, Yoshida H, Kong YY, Mak TW, Zuniga-Pflucker JC, Kroemer G, Penninger JM: Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 2001;410:549-554.
24. Kroemer G: The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nat Med 1997;3:614-620.
25. Yang E, Korsmeyer SJ: Molecular thanatopsis: A discourse on the BCL2 family and cell death. Blood 1996;88:386-401.
26. Reed JC: Bcl-2 and the regulation of programmed cell death. J Cell Biol 1994;124:1-5.
27. Schendel SL, Xie ZH, Montal MO, Matsuyama S, Montal M, Reed JC: Channel formation by antiapoptotic protein Bcl-2. Proc Natl Acad Sci USA 1997;94:5113-5118.
28. Jurgensmeier JM, Xie Z, Devereaux Q, Ellerby L, Bredesden D, Reed JC: Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci USA 1998;95:4997-5002.
29. L during apoptosis. Proc Natl Acad Sci USA 1997;94:3668.
30. Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B, Martinou JC: Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J Cell Biol 1999;144:891-901.
31. Eskes R, Desagher S, Antonsson B, Martinou JC: Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol 2000;20:929-935.
32. L. Cell 1996;87:619-628.
33. Oltvai ZN, Milliman CL, Korsmeyer SJ: Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993;74:609-619.
34. Reed JC: Double identity for proteins of the Bcl-2 family. Nature 1997;387:773-776.
35. Kharbanda S, Pandey P, Schofield L, Israels S, Roncinske R, Yoshida K, Bharti A, Yuan ZM, Saxena S, Weichselbaum R, Nalin C, Kufe D: Role for Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis. Proc Natl Acad Sci USA 1997;94:6939-6942.
36. Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X: Prevention of apoptosis by Bcl-2:Release of cytochrome c from mitochondria blocked. Science 1997;275:1129-1132.
37. Hu Y, Benedict MA, Wu D, Inohara N, Nunez G: Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Proc Natl Acad Sci USA 1998;95:4386-4391.
38. Wang HG, Rapp UR, Reed JC: Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell 1996;87:629-638.
39. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM: An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 1997;277:815-818.
40. Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, Dul E, Appelbaum ER, Eichman C, DiPrinzio R, Dodds RA, James IE, Rosenberg M, Lee JC, Young PR: Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998;273:14363-14367.
41. Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P, Huang A, Donahue CJ, Sherwood SW, Baldwin DT, Godowski PJ, Wood WI, Gurney AL, Hillan KJ, Cohen RL, Goddard AD, Botstein D, Ashkenazi A: Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 1998;396:699-703.
42. Sato T, Irie S, Kitada S, Reed JC: FAP-1:A protein tyrosine phosphatase that associates with Fas. Science 1995;268:411-415.
43. Jiang Y, Woronicz JD, Liu W, Goeddel DV: Prevention of constitutive TNF receptor 1 signaling by silencer of death domains. Science 1999;283:543-546.
44. Johnson DE: Programmed cell death regulation: Basic mechanisms and therapeutic opportunities. Leukemia 2000;14:1340-1344.
45. Condorelli G, Vigliotta G, Cafieri A, Trencia A, Andalo P, Oriente F, Miele C, Caruso M, Formisano P, Beguinot F: PED/PEA-15:An anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis. Oncogene 1999;18:4409-4415.
46. Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J, Thome M: Inhibition of death receptor signals by cellular FLIP. Nature 1997;388:190-195.
47. Kumar A, Commane M, Flickinger TW, Horvath CM, Stark GR: Defective TNF-α-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science 1997;278:1630-1632.
48. Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton-Horvat G, Farahani R, McLean M, Ikeda JE, MacKenzie A, Korneluk RG: Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 1996;379:349-353.
49. Seol DW, Billiar TR: A caspase-9 variant missing the catalytic site is an endogenous inhibitor of apoptosis. J Biol Chem 1999;274:2072-2076.
50. Lam EW, La TN: DP and E2F proteins: Coordinating transcription with cell cycle progression. Curr Opin Cell Biol 1994;6:859-866.
51. Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ: Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev 1993;7:331-342.
52. Johnson DG, Schwarz JK, Cress WD, Nevins JR: Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature 1993;365:349-352.
53. Dyson N: The regulation of E2F by pRB-family proteins. Genes Dev 1998;12:2245-2262.
54. Sherr CJ, Roberts JM: CDK inhibitors: Positive and negative regulators of G1-phase progression. Genes Dev 1999;13:1501-1512.
55. Levine AJ: p53, the cellular gatekeeper for growth and cell division. Cell 1997;88:323-331.
56. Lin D, Shields MT, Ullrich SJ, Appella E, Mercer WE: Growth arrest induced by wild-type p53 protein blocks cells prior to or near the restriction point in late G1 phase. Proc Natl Acad Sci USA 1992;89:9210-9214.
57. Owen-Schaub LB, Zhang W, Cusack JC, Angelo LS, Santee SM, Fujiwara T, Roth JA, Deisseroth AB, Zhang WW, Kruzel E et al: Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol 1995;15:3032-3040.
58. Bennett M, Macdonald K, Chan SW, Luzio JP, Simari R, Weissberg P: Cell surface trafficking of Fas: A rapid mechanism of p53-mediated apoptosis. Science 1998;282:290-293.
59. Wu GS, Burns TF, McDonald ER 3rd, Jiang W, Meng R, Krantz ID, Kao G, Gan DD, Zhou JY, Muschel R, Hamilton SR, Spinner NB, Markowitz S, Wu G, el-Deiry WS: KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet 1997;17:141-143.
60. Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B: A model for p53-induced apoptosis. Nature 1997;389:300-305.
61. Schuler M, Bossy-Wetzel E, Goldstein JC, Fitzgerald P, Green DR: p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release. J Biol Chem 2000;275:7337-7342.
62. Blattner C, Sparks A, Lane D: Transcription factor E2F-1 is upregulated in response to DNA damage in a manner analogous to that of p53. Mol Cell Biol 1999;19:3704-3713.
63. Moroni MC, Hickman ES, Denchi EL, Caprara G, Colli E, Cecconi F, Muller H, Helin K: Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol 2001;3:552-558.
64. Prives C: Signaling to p53:Breaking the MDM2-p53 circuit. Cell 1998;95:5-8.
65. Barak Y, Juven T, Haffner R, Oren M: mdm2 expression is induced by wild-type p53 activity. EMBO J 1993;12:461-468.
66. Lissy NA, Davis PK, Irwin M, Kaelin WG, Dowdy SF: A common E2F-1 and p73 pathway mediates cell death induced by TCR activation. Nature 2000;407:642-645.
67. Irwin M, Marin MC, Phillips AC, Seelan RS, Smith DI, Liu W, Flores ER, Tsai KY, Jacks T, Vousden KH, Kaelin WG Jr: Role for the p53 homologue p73 in E2F-1-induced apoptosis. Nature 2000;407:645-648.
68. Mufti GJ, Galton DA: Myelodysplastic syndromes: Natural history and features of prognostic importance. Clin Haematol 1986;15:953-971.
69. Rosati S, Mick R, Xu F, Stonys E, Le Beau MM, Larson R, Vardiman JW: Refractory cytopenia with multilineage dysplasia: Further characterization of an 'unclassifiable' myelodysplastic syndrome. Leukemia 1996;10:20-26.
70. Asano H, Ohashi H, Ichihara M, Kinoshita T, Murate T, Kobayashi M, Saito H, Hotta T: Evidence for nonclonal hematopoietic progenitor cell populations in bone marrow of patients with myelodysplastic syndromes. Blood 1994;84:588-594.
71. Shetty V, Hussaini S, Broady-Robinson L, Allampallam K, Mundle S, Borok R, Broderick E, Mazzoran L, Zorat F, Raza A: Intramedullary apoptosis of hematopoietic cells in myelodysplastic syndrome patients can be massive: Apoptotic cells recovered from high-density fraction of bone marrow aspirates. Blood 2000;96:1388-1392.
72. Clark DM, Lampert IA: Apoptosis is a common histopathological finding in myelodysplasia: The correlate of ineffective haematopoiesis. Leuk Lymphoma 1990;2:415-418.
73. Hatfill SJ, Fester ED, Steytler JG: Apoptotic megakaryocyte dysplasia in the myelodysplastic syndromes. Hematol Pathol 1992;6:87-93.
74. Raza A, Gezer S, Mundle S, Gao XZ, Alvi S, Borok R, Rifkin S, Iftikhar A, Shetty V, Parcharidou A, Loew J, Marcus B, Khan Z, Chaney C, Showel J, Gregory S, Preisler H: Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes. Blood 1995;86:268-276.
75. Mundle SD, Venugopal P, Cartlidge JD, Pandav DV, Broady-Robinson L, Gezer S, Robin EL, Rifkin SR, Klein M, Alston DE, Hernandez BM, Rosi D, Alvi S, Shetty VT, Gregory SA, Raza A: Indication of an involvement of interleukin-1β converting enzyme-like protease in intramedullary apoptotic cell death in the bone marrow of patients with myelodysplastic syndromes. Blood 1996;88:2640-2647.
76. Bogdanovic AD, Trpinac DP, Jankovic GM, Bumbasirevic VZ, Obradovic M, Colovic MD: Incidence and role of apoptosis in myelodysplastic syndrome: Morphological and ultrastructural assessment. Leukemia 1997;11:656-689.
77. Parker JE, Fishlock KL, Czepulkowski B, Mijovic A, Pagliuca A, Mufti GJ: 'Low risk' myelodysplastic syndrome is associated with excessive apoptosis and an increased ratio of proversus anti-apoptotic Bcl-2-related proteins. Br J Haematol 1998;103:1075-1082.
78. Boudard D, Sordet O, Vasselon C, Revol V, Bertheas MF, Freyssenet D, Viallet A, Piselli S, Guyotat D, Campos L: Expression and activity of caspases 1 and 3 in myelodysplastic syndromes. Leukemia 2000;14:2045-2051.
79. Ali A, Mundle SD, Ragasa D, Reza S, Shetty V, Mativi BY, Cartlidge JD, Azharuddin M, Qawi H, Dar S, Raza A: Sequential activation of caspase-1 and caspase-3-like proteases during apoptosis in myelodysplastic syndromes. J Hematother Stem Cell Res 1999;8:343-356.
80. Anzai N, Kawabata H, Hirama T, Masutani H, Ohmori M, Yoshida Y, Okuma M: Marked apoptosis of human myelomonocytic cell line P39. Significance of cellular differentiation. Leukemia 1994;8:446-453.
81. Culligan DJ, Bowen DT, May A, White D, Padua RA, Burnett AK: Refractory anaemia with preleukaemic polyclonal haemopoiesis and the emergence of monoclonal erythropoiesis on disease progression. Br J Haematol 1995;89:675-677.
82. Aizawa S, Nakano M, Iwase O, Yaguchi M, Hiramoto M, Hoshi H, Nabeshima R, Shima D, Handa H, Toyama K: Bone marrow stroma from refractory anemia of myelodysplastic syndrome is defective in its ability to support normal CD34-positive cell proliferation and differentiation in vitro. Leuk Res 1999;23:239-246.
83. Amin HM, Jilani I, Estey EH, Keating MJ, Dey AL, Manshouri T, Kantarjian HM, Estrov Z, Cortes JE, Thomas DA, Giles FJ, Albitar M: Increased apoptosis in bone marrow B lymphocytes but not T lymphocytes in myelodysplastic syndrome. Blood 2003;102:1866-1868. E-publ May 1, 2003.
84. Sloand EM, Kim S, Fuhrer M, Risitano AM, Nakamura R, Maciejewski JP, Barrett AJ, Young NS: Fas-mediated apoptosis is important in regulating cell replication and death in trisomy 8 hematopoietic cells but not in cells with other cytogenetic abnormalities. Blood 2002;100:4427-4432.
85. Kitagawa M, Saito I, Kuwata T, Yoshida S, Yamaguchi S, Takahaski M, Tanizawa T, Kamiyama R, Hirokawa K: Overexpression of tumor necrosis factor-α and interferon-γ by bone marrow cells from patients with myelodysplastic syndromes Leukemia 1997;11:2049-2054
86. Deeg HJ, Beckham C, Loken MR, Bryant E, Lesnikova M, Shulman HM, Gooley T: Negative regulators of hemopoiesis and stroma function in patients with myelodysplastic syndrome. Leuk Lymphoma 2000;37:405-414.
87. Zang DY, Goodwin RG, Loken MR, Bryant E, Deeg HJ: Expression of tumor necrosis factor-related apoptosis-inducing ligand, Apo2L, and its receptors in myelodysplastic syndrome: Effects on in vitro hemopoiesis. Blood 2001;98:3058-3065.
88. Tehranchi R, Fadeel B, Forsblom AM, Christensson B, Samuelsson J, Zhivotovsky B, Hellstrom-Lindberg E: Granulocyte colony-stimulating factor inhibits spontaneous cytochrome c release and mitochondria-dependent apoptosis of myelodysplastic syndrome hematopoietic progenitors. Blood 2003;101:1080-1086.
89. Tsoplou P, Kouraklis-Symeonidis A, Thanopoulou E, Zikos P, Orphanos V, Zoumbos N: Apoptosis in patients with myelodysplastic syndromes: Differential involvement of marrow cells in 'good' versus 'poor' prognosis patients and correlation with apoptosis-related genes. Leukemia 1999;13:1554-1563.
90. Pecci A, Travaglino E, Klersy C, Invernizzi R: Apoptosis in relation to CD34 antigen expression in normal and myelodysplastic bone marrow. Acta Haematol 2003;109:29-34.
91. Albitar M, Manshouri T, Shen Y, Liu D, Beran M, Kantarjian HM, Rogers A, Jilani I, Lin CW, Pierce S, Freireich EJ, Estey EH: Myelodysplastic syndrome is not merely 'preleukemia'. Blood 2002;100:791-798.
92. Horikawa K, Nakakuma H, Kawaguchi T, Iwamoto N, Nagakura S, Kagimoto T, Takatsuki K: Apoptosis resistance of blood cells from patients with paroxysmal nocturnal hemoglobinuria, aplastic anemia and myelodysplastic syndrome. Blood 1997;90:2716-2722.
93. Kliche KO, Andreef M: High expression of phosphatidylserine in MDS, secondary AML and normal progenitors: Comparison with primary AML (abstract). Blood 1997;90:202.
94. Levine EG, Bloomfield CD: Secondary myelodysplastic syndromes and leukaemias. Clin Haematol 1986;15:1037-1080.
95. Ridge SA, Worwood M, Oscier D, Jacobs A, Padua RA: FMS mutations in myelodysplastic, leukemic and normal subjects. Proc Natl Acad Sci USA 1990;87:1377-1380.
96. Carter G, Hughes DC, Clark RE, McCormick F, Jacobs A, Whittaker JA, Padua RA: RAS mutations in patients following cytotoxic therapy for lymphoma. Oncogene 1990;5:411-416.
97. Gale RE, Bunch C, Moir DJ, Patterson KG, Goldstone AH, Linch DC: Demonstration of developing myelodysplasia/acute myeloid leukaemia in haematologically normal patients after high-dose chemotherapy and autologous bone marrow transplantation using X-chromosome inactivation patterns. Br J Haematol 1996;93:53-58.
98. Bowen DT, Wu PS, Talathi J, Smith G, Hay A, Keenan N, Thomas GE: Prior to presentation of pre-leukaemia - Blood count abnormalities and the latency of disease development. Leuk Res 2003;27:S4.
99. Kurotaki H, Tsushima Y, Nagai K, Yagihashi S: Apoptosis, bcl-2 expression and p53 accumulation in myelodysplastic syndrome, myelodysplastic-syndrome-derived acute myelogenous leukemia and de novo acute myelogenous leukemia. Acta Haematol 2000;102:115-123.
100. Bouscary D, Chen YL, Guesnu M, Picard F, Viguier F, Lacombe C, Dreyfus F, Fontenay-Roupie M: Activity of the caspase-3/CPP32 enzyme is increased in 'early stage' myelodysplastic syndromes with excessive apoptosis, but caspase inhibition does not enhance colony formation in vitro. Exp Hematol 2000;28:784-791.
101. Kitagawa M, Kamiyama R, Kasuga T: Expression of the proliferating cell nuclear antigen in bone marrow cells from patients with myelodysplastic syndromes and aplastic anemia. Hum Pathol 1993;24:359-363.
102. Jensen IM: Myelopoiesis in myelodysplasia evaluated by multiparameter flow cytometry. Leuk Lymphoma 1995;20:17-25.
103. Duhrsen U, Hossfeld DK: Stromal abnormalities in neoplastic bone marrow diseases. Ann Hematol 1996;73:53-70.
104. Tricot G, De Wolf Peeters C, Vlietinck R, Verwilghen RL: Bone marrow histology in myelodysplastic syndromes. II. Prognostic value of abnormal localization of immature precursors in MDS. Br J Haematol 1984;58:217-225.
105. Mangi MH, Mufti GJ: Primary myelodysplastic syndromes: Diagnostic and prognostic significance of immunohistochemical assessment of bone marrow biopsies. Blood 1992;79:198-205.
106. Tennant GB, Walsh V, Truran LN, Edwards P, Mills KI, Burnett AK: Abnormalities of adherent layers grown from bone marrow of patients with myelodysplasia. Br J Haematol 2000;111:853-862.
107. Aizawa S, Hiramoto M, Hoshi H, Toyama K, Shima D, Handa H: Establishment of stromal cell line from an MDS RA patient which induced an apoptotic change in hematopoietic and leukemic cells in vitro. Exp Hematol 2000;28:148-155.
108. Bowen D, Yancik S, Bennett L, Culligan D, Resser K: Serum stem cell factor concentration in patients with myelodysplastic syndromes. Br J Haematol 1993;85:63-66.
109. Maurer AB, Ganser A, Buhl R, Seipelt G, Ottmann OG, Mentzel U, Geissler RG, Hoelzer D: Restoration of impaired cytokine secretion from monocytes of patients with myelodysplastic syndromes after in vivo treatment with GM-CSF or IL-3. Leukemia 1993;7:1728-1733.
110. Visani G, Zauli G, Tosi P, Fogli M, Cenacchi A, Finelli C, Gamberi B, Ottaviani E, Manfoi S, Tura S: Impairment of GM-CSF production in myelodysplastic syndromes. Br J Haematol 1993;84:227-231.
111. Gidali J, Feher I, Hollan SR: Blast colony-forming cell-binding capacity of bone marrow stroma from myelodysplastic patients. Stem Cells 1996;14:577-583.
112. Greenberg PL, Mackichan ML, Negrin R, Renick M, Ginzton N: Production of granulocyte colony-stimulating factor by normal and myelodysplastic syndrome peripheral blood cells (abstract). Blood 1990;76:(suppl 1):146.
113. Hellstrom-Lindberg E, Kanter-Lewensohn L, Ost A: Morphological changes and apoptosis in bone marrow from patients with myelodysplastic syndromes treated with granulocyte-CSF and erythropoietin. Leuk Res 1997;21:415-425.
114. Verhoef GEG, De Schouwer P, Ceuppens JL, Van Damme J, Goossens W, Boogaerts MA: Measurement of serum cytokine levels in patients with myelodysplastic syndromes. Leukemia 1992;12:1268-1272.
115. Shetty V, Mundle S, Alvi S, Showel M, Broady-Robinson L, Dar S, Borok R, Showel J, Gregory S, Rifkin S, Gezer S, Parcharidou A, Venugopal P, Shah R, Hernandez B, Klein M, Alston D, Robin E, Dominquez C, Raza A: Measurement of apoptosis, proliferation and three cytokines in 46 patients with myelodysplastic syndromes. Leuk Res 1996;20:891-900.
116. + myelodysplastic cells is associated with intracellular redox changes and elevated plasma tumour necrosis factor-α concentration. Br J Haematol 1997;99:625-631.
117. Gersuk GM, Beckham C, Loken MR, Kiener P, Anderson JE, Farrand A, Troutt AB, Ledbetter JA, Deeg HJ: A role for tumour necrosis factor-α, Fas and Fas ligand in marrow failure associated with myelodysplastic syndrome. Br J Haematol 1998;103:176-188.
118. Mundle SD, Reza S, Ali A, Mativi Y, Shetty V, Venugopal P, Gregory SA, Raza A: Correlation of tumor necrosis factor-α with high Caspase 3-like activity in myelodysplastic syndromes. Cancer Lett 1999;140:201-207.
119. Sawanobori M, Yamaguchi S, Hasegawa M, Inoue M, Suzuki K, Kamiyama R, Hirokawa K, Kitagawa M: Expression of TNF receptors and related signaling molecules in the bone marrow from patients with myelodysplastic syndromes. Leuk Res 2003;27:583-591.
120. Musto P, Matera R, Minervini MM, Checchia de Ambrosio C, Bodenizza C, Falcone A, Carotenuto M: Low serum levels of tumor necrosis factor and interleukin-1β in myelodysplastic syndromes responsive to recombinant erythropoietin. Haematologica 1994;79:265-268.
121. Stasi R, Brunetti M, Bussa S, Conforti M, Martin LS, Presa ML, Bianchi M, Parma A, Pagano A: Serum levels of tumour necrosis factor-α predict response to recombinant human erythropoietin in patients with myelodysplastic syndrome. Clin Lab Haematol 1997;19:197-201.
122. Kitagawa M, Kamiyama R, Kasuga T: Increase in number of bone marrow macrophages in patients with myelodysplastic syndromes. Eur J Haematol 1993;51:56-58.
123. Janowska-Wieczorek A, Belch AR, Jacobs A, Bowen D, Padua RA, Paietta E, Stanley ER: Increased circulating colony-stimulating factor-1 in patients with preleukemia, leukemia and lymphoid malignancies Blood 1991;77:1796-1803.
124. Tobal K, Pagliuca A, Bhatt B, Bailey N, Layton DM, Mufti GJ: Mutation of the human FMS gene (M-CSF receptor) in myelodysplastic syndromes and acute myeloid leukemia. Leukemia 1990;4:486-489.
125. Plasilova M, Zivny J, Jelinek J, Neuwirtova R, Cermak J, Necas E, Andera L, Stopka T: TRAIL (Apo2L) suppresses growth of primary human leukemia and myelodysplasia progenitors. Leukemia 2002;16:67-73.
126. Bouscary D, De Vos J, Guesnu M, Jondeau K, Viguier F, Melle J, Picard F, Dreyfus F, Fontenay-Roupie M: Fas/Apo-1 (CD95) expression and apoptosis in patients with myelodysplastic syndromes. Leukemia 1997;11:839-845.
127. Claessens YE, Bouscary D, Dupont JM, Picard F, Melle J, Gisselbrecht S, Lacombe C, Dreyfus F, Mayeux P, Fontenay-Roupie M: In vitro proliferation and differentiation of erythroid progenitors from patients with myelodysplastic syndromes: Evidence for Fas-dependent apoptosis. Blood 2002;99:1594-1601.
128. Hellstrom-Lindberg E, Schmidt-Mende J, Forsblom AM, Christensson B, Fadeel B, Zhivotovsky B: Apoptosis in refractory anaemia with ringed sideroblasts is initiated at the stem cell level and associated with increased activation of caspases. Br J Haematol 2001;112:714-726.
129. Mundle SD, Mativi BY, Bagai K, Feldman G, Cheema P, Gautam U, Reza S, Cartlidge JD, Venugopal P, Shetty V, Gregory SA, Robin E, Rifkin S, Shah R, Raza A: Spontaneous down-regulation of Fas-associated phosphatase-1 may contribute to excessive apoptosis in myelodysplastic marrows. Int J Haematol 1999;70:83-90.
130. Young NS, Maciejewski J: The pathophysiology of acquired aplastic anemia. N Engl J Med 1997;336:1365-1372.
131. Molldrem JJ, Jiang YZ, Stetler-Stevenson M, Mavroudis D, Hensel N, Barrett AJ: Hematological response of patients with myelodysplastic syndrome to antithymocyte globulin is associated with a loss of lymphocyte-mediated inhibition of CFU-GM and alterations in T-cell receptor Vβ profiles. Br J Haematol 1998;102:1314-1322.
132. List AF, Glinsmann-Gibson B, Spier C, Taetle R: In vitro and in vivo response to cyclosporine A in myelodysplastic syndromes: Identification of a hypocellular subset responsive to immune suppression (abstract). Blood 1992;80:28.
133. Molldrem JJ, Caples M, Mavroudis D, Plante M, Young NS, Barrett AJ: Antithymocyte globulin for patients with myelodysplastic syndrome. Br J Haematol 1997;99:699-705.
134. Jonasova A, Neuwirtova R, Cermak J, Vozobulova V, Mocikova K, Siskova M, Hochova I: Cyclosporin A therapy in hypoplastic MDS patients and certain refractory anaemias without hypoplastic bone marrow. Br J Haematol 1998;100:304-309.
135. Bessho F, Ohnishi H, Tabuchi K, Kobayashi M, Hayashi Y: Significance of electron-dense deposits in the mitochondrial matrix of erythroid precursors in aplastic anaemia and myelodysplastic syndrome. Br J Haematol 1999;105:149-154.
136. Van de Loosdrecht AA, Brada SJ, Blom NR, Hendriks DW, Smit JW, van den Berg E, de Wolf JT, Vellenga E: Mitochondrial disruption and limited apoptosis of erythroblasts are associated with high-risk myelodysplasia. An ultrastructural analysis. Leuk Res 2001;25:385-393.
137. Gattermann N, Retzlaff S, Wang YL, Hofhaus G, Heinisch J, Aul C, Schneider W: Heteroplasmic point mutations of mitochondrial DNA affecting subunit I of cytochrome c oxidase in two patients with acquired idiopathic sideroblastic anemia. Blood 1997;90:4961-4972.
138. Reddy PL, Shetty VT, Dutt D, York A, Dar S, Mundle SD, Allampallam K, Alvi S, Galili N, Saberwal GS, Anthwal S, Shaikh M, Suleman S, Kamal SY, Raza A: Increased incidence of mitochondrial cytochrome c-oxidase gene mutations in patients with myelodysplastic syndromes. Br J Haematol 2002;116:564-575.
139. Dror Y: The role of mitochondrial-mediated apoptosis in a myelodysplastic syndrome secondary to congenital deletion of the short arm of chromosome 4. Exp Hematol 2003;31:211-217.
140. Luna-Fineman S, Shannon KM, Atwater SK, Davis J, Masterson M, Ortega J, Sanders J, Steinherz P, Weinberg V, Lange BJ: Myelodysplastic and myeloproliferative disorders of childhood: A study of 167 patients. Blood 1999;93:459-466.
141. D'Andrea AD, Grompe M: Molecular biology of Fanconi anemia: Implications for diagnosis and therapy. Blood 1997;90:1725-1736.
142. Bollag G, Clapp DW, Shih S, Adler F, Zhang YY, Thompson P, Lange BJ, Freedman MH, McCormick F, Jacks T, Shannon K: Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nat Genet 1996;12:144-148.
143. Levine EG, Bloomfield CD: Secondary myelodysplastic syndromes and leukaemias. Clin Haematol 1986;15:1037-1080.
144. West RR, Stafford DA, White DA, Bowen DT, Padua, RA: Cytogenetic abnormalities in the myelodysplastic syndromes and occupational or environmental exposure Blood 2000;95;2093-2097.
145. Chen H, Sandler DP, Taylor JA, Shore DL, Liu E, Bloomfield CD, Bell DA: Increased risk for myelodysplastic syndromes in individuals with glutathione transferase theta 1 (GSTT1) gene defect. Lancet 1996;347:295-296.
146. Felix CA, Walker AH, Lange BJ, Williams TM, Winick NJ, Cheung NV, Lovett BD, Nowell PC, Blair IA, Rebbeck TR: Association of CYP3A4 genotype with treatment-related leukemia. Proc Natl Acad Sci USA 1998;95:13176-13181.
147. + cells from normal and myelodysplastic bone marrow. Blood 2002;100:3553-3560.
148. Ohyashiki JH, Iwama H, Yahata N, Ando K, Hayashi, Shay JW, Ohyashiki K: Telomere stability is frequently impaired in high-risk groups of patients with myelodysplastic syndromes. Clin Cancer Res 1999;5:1155-1160.
149. Boultwood J, Fidler C, Kusec R, Rack K, Elliott JW, Atoyebi O, Chapman R, Oscier DG, Wainscoat JS: Telomere length in myelodysplastic syndromes. Am J Hematol 1997;56:266-271.
150. Bellamy WT, Richter L, Frutiger Y, Grogan TM: Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res 1999;59:728-733.
151. Pruneri G, Bertolini F, Soligo D, Carboni N, Cortelezzi A, Ferrucci PF, Buffa R, Lambertenghi-Deliliers G, Pezzella F: Angiogenesis in myelodysplastic syndromes. Br J Cancer 1999;81:1398-1401.
152. Aguayo A, Kantarjian H, Manshouri T, Gidel C, Estey E, Thomas D, Koller C, Estrov Z, O'Brien S, Keating M, Freireich E, Albitar M: Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 2000; 96:2240-2245.
153. Bellamy WT, Richter L, Sirjani D, Roxas C, Glinsmann-Gibson B, Frutiger Y, Grogan TM, List AF: Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. Blood 2001;97:1427-1434.
154. Zachary I: Vascular endothelial growth factor. Int J Biochem Cell Biol 1998;30:1169-1174.
155. Ziegler BL, Valtieri M, Porada GA, De Maria R, Muller R, Masella B, Gabbianelli M, Casella I, Pelosi E, Bock T, Zanjani ED, Peschle C: KDR receptor: A key marker defining hematopoietic stem cells. Science 1999;285:1553-1558.
156. Borset M, Seidel C, Hjorth-Hansen H, Waage A, Sundan A: The role of hepatocyte growth factor and its receptor c-Met in multiple myeloma and other blood malignancies. Leuk Lymphoma 1999;32:249-256.
157. Jia L, Srinivasula SM, Liu FT, Newland AC, Fernandes-Alnemri T, Alnemri ES, Kelsey SM: Apaf-1 protein deficiency confers resistance to cytochrome c-dependent apoptosis in human leukemic cells. Blood 2001;98:414-421.
158. Preudhomme C, Vachee A, Lepelley P, Vanrumbeke M, Zandecki M, Quesnel B, Cosson A, Fenaux P: Inactivation of the retinoblastoma gene appears to be very uncommon in myelodysplastic syndromes. Br J Haematol 1994;87:61-67.
159. Mundle SD, Mativi BY, Cartlidge JD, Dangerfield B, Broady-Robinson L, Li B, Shetty V, Venugopal P, Gregory SA, Preisler HD, Raza A: Signal antonymy unique to myelodysplastic marrows correlates with altered expression of E2F1. Br J Haematol 2000;109:376-381.
160. Sugimoto K, Hirano N, Toyoshima H, Chiba S, Mano H, Takaku F, Yazaki Y, Hirai H: Mutations of the p53 gene in myelodysplastic syndrome (MDS) and MDS-derived leukemia. Blood 1993;81:3022-3026.
161. Tamaki H, Ogawa H, Ohyashiki K, Ohyashiki JH, Iwama H, Inoue K, Soma T, Oka Y, Tatekawa T, Oji Y, Tsuboi A, Kim EH, Kawakami M, Fuchigami K, Tomonaga M, Toyama K, Aozasa K, Kishimoto T, Sugiyama H: The Wilms' tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes. Leukemia 1999;13:393-399.
162. Maheswaran S, Englert C, Bennett P, Heinrich G, Haber DA: TheWT1 gene product stabilizes p53 and inhibits p53-mediated apoptosis. Genes Dev 1995;9:2143-2156.
163. Ceballos E, Delgado MD, Gutierrez P, Richard C, Muller D, Eilers M, Ehinger M, Gullberg U, Leon J: c-Myc antagonizes the effect of p53 on apoptosis and p21WAF1 transactivation in K562 leukemia cells. Oncogene 2000;19:2194-2204.
164. Bodner SM, Naeve CW, Rakestraw KM, Jones BG, Valentine VA, Valentine MB, Luthardt FW, Willman CL, Raimondi SC, Downing JR, Roussel MF, Sherr CJ, Look AT: Cloning and chromosomal localization of the gene encoding human cyclin D-binding Myb-like protein (hDMP1). Gene 1999;229:223-228.
165. INK4b gene in myelodysplastic syndromes. Blood 1997;90:1403-1409.
166. Quesnel B, Guillerm G, Vereecque R, Wattel E, Preudhomme C, Bauters F, Vanrumbeke M Fenaux P: Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression. Blood 1998;91:2985-2990.
167. Delia D, Aiello A, Soligo D, Fontanella E, Melani C, Pezzella F, Pierotti MA, Della-Porta G: bcl-2 proto-oncogene expression in normal and neoplastic human myeloid cells. Blood 1992;79:1291-1298.
168. Davis RE, Greenberg PL: Bcl-2 expression by myeloid precursors in myelodysplastic syndromes: Relation to disease progression. Leuk Res 1998;22:767-777.
169. Invernizzi R, Pecci A, Bellotti L, Ascari E: Expression of p53, bcl-2 and ras oncoproteins and apoptosis levels in acute leukaemias and myelodysplastic syndromes. Leuk Lymphoma 2001;42:481-489.
170. Boudard D, Vasselon C, Bertheas MF, Jaubert J, Mounier C, Reynaud J, Viallet A, Chautard S, Guyotat D, Campos L: Expression and prognostic significance of Bcl-2 family proteins in myelodysplastic syndromes. Am J Hematol 2002;70:115-125.
171. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079-2088.
172. Jia L, Macey MG, Yin Y, Newland AC, Kelsey SM: Subcellular distribution and redistribution of Bcl-2 family proteins in human leukemia cells undergoing apoptosis. Blood 1999;93:2353-2359.
173. Hahne M, Rimoldi D, Schroter M, Romero P, Schreier M, French LE, Schneider P, Bornand T, Fontana A, Lienard D, Cerottini J, Tschopp J: Melanoma cell expression of Fas-(Apo-1/CD95) ligand: Implications for tumor immune escape. Science 1996;274:1363-1366.
174. Gupta P, Niehans GA, LeRoy SC, Gupta K, Morrison VA, Schultz C, Knapp DJ, Kratzke RA: Fas ligand expression in the bone marrow in myelodysplastic syndromes correlates with FAB subtype and anemia, and predicts survival. Leukemia 1999;13:44-53.
175. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD: World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, Nov 1997. J Clin Oncol 1999;17:3835-3849.
176. Greenberg P, Taylor K, Larson R, Koeffler P, Negrin R, Saba H, Ganser A, Jakubowski A, Gabrilove J, Mufti G, Cruz J, Hammond W, Broudy V, Langley GR, Keating A, Vardiman J, Lamborn K, Brown S: Phase III randomized multicenter trial of G-CSF vs. observation for myelodysplastic syndromes (abstract). Blood 1993;82:196.
177. Hellstrom-Lindberg E: Efficacy of erythropoietin in the myelodysplastic syndromes: A meta-analysis of 205 patients from 17 studies. Br J Haematol 1995;89:67-71.
178. Negrin RS, Stein R, Doherty K, Cornwell J, Vardiman J, Krantz S, Greenberg PL: Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor and erythropoietin: Evidence for in vivo synergy. Blood 1996;87:4076-4081.
179. Hellstrom-Lindberg E, Ahlgren T, Beguin Y, Carlsson M, Carneskog J, Dahl IM, Dybedal I, Grimfors G, Kanter-Lewensohn L, Linder O, Luthman M, Lofvenberg E, Nilsson-Ehle H, Samuelsson J, Tangen JM, Winqvist I, Oberg G, Osterborg A, Ost A: Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: Results from a randomized phase II study and long-term follow-up of 71 patients. Blood 1998;92:68-75.
180. Mantovani L, Lentini G, Hentschel B, Wickramanayake PD, Loeffler M, Diehl V, Tesch H: Treatment of anaemia in myelodysplastic syndromes with prolonged administration of recombinant human granulocyte colony-stimulating factor and erythropoietin. Br J Haematol 2000;109:367-375.
181. Silva M, Grillot D, Benito A, Richard C, Nunez G, Fernandez-Luna JL: Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2. Blood 1996;88:1576-1582.
182. Schmidt-Mende J, Tehranchi R, Forsblom AM, Joseph B, Christensson B, Fadeel B, Zhivotovsky B, Hellstrom-Lindberg E: Granulocyte colony-stimulating factor inhibits Fas-triggered apoptosis in bone marrow cells isolated from patients with refractory anemia with ringed sideroblasts. Leukemia 2001;15:742-751.
183. Dibbert B, Weber M, Nikolaizik WH, Vogt P, Schoni MH, Blaser K, Simon HU: Cytokine-mediated Bax deficiency and consequent delayed neutrophil apoptosis: A general mechanism to accumulate effector cells in inflammation. Proc Natl Acad Sci USA 1999;96:13330-13335.
184. Raza A, Qawi H, Andric T, Dar S, Lisak L, Huang RW, Venugopal P, Gezer S, Gregory SA, Hsu WT, Loew J, Robin E, Rifkin S, Shah R, Divgi A, Taylor R, Grosset A: Pentoxifylline, ciprofloxacin and dexamethasone improve the ineffective hematopoiesis in myelodysplastic syndrome patients: Malignancy. Hematol 2000;5:275-284.
185. Rosenfeld C, Bedell C: Pilot study of recombinant human soluble tumor necrosis factor receptor (TNFR:Fc) in patients with low-risk myelodysplastic syndrome. Leuk Res 2002;26:721-724.
186. Maciejewski JP, Risitano AM, Sloand EM, Wisch L, Geller N, Barrett JA, Young NS, Ristiano AM: A pilot study of the recombinant soluble human tumour necrosis factor receptor (p75)-Fc fusion protein in patients with myelodysplastic syndrome. Br J Haematol 2002;117:119-126.
187. Denmeade SR, Lin XS, Tombal B, Isaacs JT: Inhibition of caspase activity does not prevent the signaling phase of apoptosis in prostate cancer cells. Prostate 1999;39:269-279.
188. Bossy-Wetzel E, Newmeyer DD, Green DR: Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 1998;17:37-49.
189. List AF, Heaton R, Glinsmann-Gibson B, Capizzi RL: Amifostine stimulates formation of multipotent and erythroid bone marrow progenitors. Leukemia 1998;12:1596-1602.
190. North S, El-Ghissassi F, Pluquet O, Verhaegh G, Hainaut P: The cytoprotective aminothiol WR1065 activates p21waf-1 and down regulates cell cycle progression through a p53-dependent pathway. Oncogene 2000;19:1206-1214.
191. List AF: Anti-apoptotic therapy: Over-riding the cell death program in MDS. Leuk Res 1999;23:S77.
192. Preisler HD, Li B, Yang BL, Huang RW, Devemy E, Venugopal P, Tao M, Chopra H, Gregory SA, Adler S, Sivaraman S, Toofanfard P, Jajeh A, Galvez A, Robin E: Suppression of telomerase activity and cytokine messenger RNA levels in acute myelogenous leukemia cells in vivo in patients by amifostine and interleukin-4. Clin Cancer Res 2000;6:807-812.
193. List AF, Brasfield F, Heaton R, Glinsmann-Gibson B, Crook L, Taetle R, Capizzi R: Stimulation of hematopoiesis by amifostine in patients with myelodysplastic syndrome. Blood 1997;90:3364-3369.
194. Bowen DT, Denzlinger C, Brugger W, Culligan D, Gelly K, Adlakha S, Groves M, Hepburn M, Kanz L: Poor response rate to a continuous schedule of amifostine therapy for 'low/intermediate risk' myelodysplastic patients. Br J Haematol 1998;103:785-787.
195. Grossi A, Fabbri A, Santini V, Leoni F, Nozzoli C, Longo G, Pagliai G, Ciolli S, Rossi Ferrini P: Amifostine in the treatment of low-risk myelodysplastic syndromes. Haematologica 2000;85:367-371.
196. Hellstrom-Lindberg E, Willman C, Barrett AJ, Saunthararajah Y: Achievements in understanding and treatment of myelodysplastic syndromes. Hematology (Am Soc Hematol Educ Program) 2000;110-132.
197. Raza A, Meyer P, Dutt D, Zorat F, Lisak L, Nascimben F, du Randt M, Kaspar C, Goldberg C, Loew J, Dar S, Gezer S, Venugopal P, Zeldis J: Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood 2001;98:958-965.
198. Zorat F, Shetty V, Dutt D, Lisak L, Nascimben F, Allampallam K, Dar S, York A, Gezer S, Venugopal P, Raza A: The clinical and biological effects of thalidomide in patients with myelodysplastic syndromes. Br J Haematol 2001;115:881-894.
199. Steins MB, Padro T, Ruiz S, Kropff M, Kienast J, Kessler T, Buechner T, Berdel WE, Mesters RM: Efficacy and safety of thalidomide in patients with acute myeloid leukemia. Blood 2002;99:834.
200. Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ, Patterson RT, Stirling DI, Kaplan G: Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-α. J Immunol 1999;163:380-386.
201. Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, Lin B, Podar K, Gupta D, Chauhan D, Treon SP, Richardson PG, Schlossman RL, Morgan GJ, Muller GW, Stirling DI, Anderson KC: Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001;98:210-216.
202. List AF, Tate W, Glinsmann-Gibson B, Baker A: The immunomodulatory thalidomide analog CC5013 inhibits trophic response to VEGF in AML cells by abolishing cytokine-induced P13-Akt activation (abstract). Blood 2002;100:139.
203. List AF, Kurtin SE, Glnismann-Gibson BJ, Bellamy WT, Buresh AJ, Waddleton D, Knight R: High erythropoietic remitting activity of the immunomodulatory thalidomide analog CC5013, in patients with myelodysplastic syndrome (abstract). Blood 2002;100:96.
204. Wijermans P, Lübbert M, Verhoef G, Bosly A, Ravoet C, Andre M, Ferrant A: Low-dose 5-aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: A multicenter phase II study in elderly patients. J Clin Oncol 2000;18:956-962.
205. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer C, Holland JF: Randomized controlled trial of azacytidine in patients with the myelodysplastic syndrome: A study of the Cancer and Leukemia Group B. J Clin Oncol 2002;20:2429-2440.
206. Reuter CW, Morgan MA, Bergmann L: Targeting the Ras signaling pathway: A rational, mechanism-based treatment for hematologic malignancies? Blood 2000;96:1655-1669.
207. Kurzrock R, Kantarjian HM, Cortes JE, Wright J, Wilson, E, Sebti S: Farnesyl protein transferase inhibitor (FTI) Zarnestra™ (R115777) in patients with myelodysplastic syndrome: Clinical and biological aspects. Leuk Res 2003;27:S105.
208. Mesters RM, Padro T, Bieker R, Steins M, Kreuter M, Goner M, Kelsey S, Scigalla P, Fiedler W, Buchner T, Berdel WE: Stable remission after administration of the receptor tyrosine kinase inhibitor SU5416 in a patient with refractory acute myeloid leukemia. Blood 2001;98:241-243.
209. Smolich BD, Yuen HA, West KA, Giles FJ, Albitar M, Cherrington JM: The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. Blood 2001;97:1413-1421.
210. Giles FJ, Stopeck AT, Silverman LR, Lancet JE, Cooper MA, Hannah AL, Cherrington JM, O'Farrell AM, Yuen HA, Louie SG, Hong W, Cortes JE, Verstovsek S, Albitar M, O'Brien SM, Kantarjian HM, Karp JE: SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood 2003;102:795-801.
211. Albitar M, Smolich BD, Cherrington JM, O'Farrell M, Karp JE, Stopeck A, Zangari M, Lancet JE, Silverman LR, Giles F: Effects of SU5416 on angiogenic factors, proliferation and apoptosis in patients with hematological malignancies (abstract). Blood 2001;98:110.
212. Liekens S, DeClercq E, Neyts J: Angiogenesis: Regulators and clinical applications. Biochem Pharmacol 2001;61:253-270.
213. Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP: A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 1997;385:729-733.
214. Kayagaki N, Kawasaki A, Ebata T, Ohmoto H, Ikeda S, Inoue S, Yoshino K, Okumura K, Yagita H: Metalloproteinase-mediated release of human Fas ligand. J Exp Med 1995;182:1777-1783.
215. List AF, Kurtin S, Callander N, Foran J, Rabinowitz I, Gibson B, Bellamy W, Bennett J, Collier M: Randomized, double-blind phase II study of the matrix metalloprotease (MMP) inhibitor, AG3340 (Prinomastat™) in patients with myelodysplastic syndrome (abstract). Blood 2002;100:789.
216. Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, Stone RM, Kalaycio M, Scheinberg DA, Steinherz P, Sievers EL, Coutre S, Dahlberg S, Ellison R, Warrell RP Jr: United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001;19:3852-3860.
217. Cheson BD, Zwiebel JA, Dancey J, Murgo A: Novel therapeutic agents for the treatment of myelodysplastic syndromes. Semin Oncol 2000;27:560-577.
218. Chen YC, Lin-Shiau SY, Lin JK: Involvement of reactive oxygen species and caspase 3 activation in arsenite-induced apoptosis. J Cell Physiol 1998;177:324-333.
219. Roboz GJ, Dias S, Lam G, Lane WJ, Soignet SL, Warrell RP Jr, Rafii S: Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis. Blood 2000;96:1525-1530.
220. Donelli A, Chiodino C, Panissidi T, Roncaglia R, Torelli G: Might arsenic trioxide be useful in the treatment of advanced myelodysplastic syndromes? Haematologica 2000;85:1002-1003.
221. List AF, Schiller GJ, Mason J, Douer D, Paradise C: Trisenox® (arsenic trioxide, ATO) in patients with myelodysplastic syndromes: Preliminary findings in a phase II clinical study (abstract). Blood 202;100:790.
222. Raza A, Lisak LA, Tahir S, Billmeier JM, Willmann HS, Alvi MI, Patkar S, Khan T, Rizvi A, Venugopal P, Gezer S, Mundle SD, Reddy PL: Trilineage responses to arsenic trioxide (Trisenox®) and thalidomide in patients with myelodysplastic syndromes, particularly those with inv(3)(q21q26.2) (abstract). Blood 2002;100:795.
223. Lepelley P, Campergue L, Grardel N, Preudhomme C, Cosson A, Fenaux P: Is apoptosis a massive process in myelodysplastic syndromes? Br J Haematol 1996;95:368-371.
224. Kitagawa M, Yamaguchi S, Takahashi M, Tanizawa T, Hirokawa K, Kamiyama R: Localization of Fas and Fas ligand in bone marrow cells demonstrating myelodysplasia. Leukemia 1998;12:486-492.
225. Hellstrom-Lindberg E, Willman C, Barrett AJ, Saunthararajah Y RE: Apoptotic index by Annexin V flow cytometry: Adjunct to morphologic and cytogenetic diagnosis of myelodysplastic syndromes. Cytometry 2001;46:28-32.