The molecular biology of erythropoietin

Nephrology Dialysis Transplantation

Volumn 14, Issue SUPPL. 2, 1999, Pages 22-28

  Lacombe, Catherine ^a,b   Mayeux, P ^a  

^a INSERM   (France)

^b Hôpital Cochin ^*  (France)

Author keywords

Erythropoietin; Erythropoietin receptor; Hypoxia; Signal transduction

Indexed keywords

CELL SURFACE RECEPTOR; ERYTHROPOIETIN; ERYTHROPOIETIN RECEPTOR; PROTEIN TYROSINE KINASE; RECOMBINANT ERYTHROPOIETIN;

ANEMIA; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL SURVIVAL; CONFERENCE PAPER; ENHANCER REGION; ERYTHROID PRECURSOR CELL; HUMAN; HYPOXIA; KIDNEY; KIDNEY FAILURE; LIVER; MOLECULAR BIOLOGY; PRIORITY JOURNAL; PROTEIN CROSS LINKING;

ANEMIA; ANIMALS; ERYTHROPOIESIS; ERYTHROPOIETIN; HUMANS; RECEPTORS, ERYTHROPOIETIN; SIGNAL TRANSDUCTION;

EID: 0032916880     PISSN: 09310509     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Conference Paper

References (110)

1. Miyake T, Kung CK, Goldwasser E. Purification of human erythropoietin. J Biol Chem 1977; 252: 5558-5564
2. Jacobs K, Shoemaker C, Rudersdorf R et al. Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 1985; 313: 806-810
3. Lin FK, Suggs S, Lin CH et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci USA 1985; 82: 7580-7584
4. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med 1987; 316: 73-78
5. Gregory CJ, Eaves AC. Human marrow cells capable of erythropoietic differentiation in vitro: definition of three erythroid colony responses. Blood 1977; 49: 855-864
6. Gregory CJ, Eaves AC. Three stages of erythropoietic progenitor cell differentiation distinguished by a number of physical and biologic properties. Blood 1978; 51: 527-537
7. Wu H, Liu X, Jaenisch R, Lodish HF. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 1995; 83: 59-67
8. Lin C-S, Lim SK, D'Agati V, Costantini F. Differential effects of an erythropoietin receptor gene disruption on primitive and definitive eythropoiesis. Genes Dev 1996; 10: 154-164
9. Spivak JL, Pham T, Isaacs M, Hankins WD. Erythropoietin is both a mitogen and a survival factor. Blood 1991; 77: 1228-1233
10. Hermine O, Mayeux P, Titeux M et al. Granulocyte-macrophage colony-stimulating factor and erythropoietin act competitively to induce two different programs of differentiation in the human pluripotent cell line UT-7. Blood 1992; 80: 3060-3069
11. Komatsu N, Nakauchi H, Miwa A et al. Establishment and characterization of a human leukemic cell line with megakaryocytic features: dependency on granulocyte-macrophage colony stimulating factor, interleukin 3, or erythropoietin for growth and survival. Cancer Res 1991; 51: 341-345
12. D'Andrea AD, Yoshimura A, Youssoufian H, Zon L, Koo J, Lodish HF. The cytoplasmic region of the erythropoietin receptor contains non overlapping positive and negative growth-regulatory domains. Mol Cell Biol 1991; 11: 1980-1987
13. Miura O, D'Andrea A, Kabat D, Ihle JN. Induction of tyrosine phosphorylation by the erythropoietin receptor correlates with mitogenesis. Mol Cell Biol 1991; 11: 4895-4902
14. Quelle DE, Wojchowski DM. Localized cytosolic domains of the erythropoietin receptor regulate growth signaling and downmodulate responsiveness to granulocyte-macrophage colony-stimulating factor. Proc Natl Acad Sci USA 1991; 88: 4801-4805
15. Chiba T, Kishi A, Sugiyama M et al. Functionally essential cytoplasmic domain of the erythropoietin receptor. Biochem Biophys Res Commun 1992; 186: 1236-1241
16. Feger F, Dubart A, Lacout C et al. Ectopic expression of the erythropoietin receptor in a murine interleukin 6-dependent plasmacytoma cell line (TEPC-2027) confers proliferative responsiveness to erythropoietin. Blood 1997; 89: 435-445
17. 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
18. D'Andrea AD, Zon LI. Erythropoietin receptor: subunit structure and activation. J Clin Invest 1990; 86: 681-687
19. Sawada K, Krantz SB, Dai C-H et al. Purification of human blood burst-forming units-erythroid and demonstration of the evolution of erythropoietin receptor. J Cell Physiol 1990; 142: 219-230
20. Broudy VC, Lin N, Brice M, Nakamoto B, Papayannopoulou T. Erythropoietin receptor characteristics on primary human erythroid cells. Blood 1991; 77: 2583-2590
21. Wickrema A, Krantz SB, Winkelmann JC, Bondurant MC. Differentiation and erythropoietin receptor gene expression in human erythroid progenitor cells. Blood 1992; 80: 1940-1949
22. Fukamachi H, Saito T, Tojo A, Kitamura T, Urabe A, Takaku F. Binding of erythropoietin to CFU-E derived from fetal mouse liver cells. Exp Hematol 1987; 15: 833-837
23. Mayeux P, Billat C, Jacquot R. The erythropoietin receptor of rat erythroid progenitor cell: characterization and affinity cross-linkage. J Biol Chem 1987; 262: 13985-13990
24. Fraser JK, Tan AS, Lin FJ, Berridge MV. Expression of high affinity binding sites for erythropoietin on rat and mouse megakaryocytes. Exp Hematol 1989; 17: 10-16
25. Yoshida T, Ishida Y, Sasaki H, Inoue T, Kaku K, Kaneko T. Expression of high affinity binding sites for erythropoietin on L8057 cells, a mouse megakaryoblastic cell line, associated with cell differentiation. Am J Hematol 1992; 39: 32-38
26. Sawyer ST, Krantz SB, Sawada KI. Receptors for erythropoietin in mouse and human erythroid cells and placenta. Blood 1989; 74: 103-109
27. Anagnostou A, Lee ES, Kessimian N, Levinson R, Steiner M. Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci USA 1990; 87: 5978-5982
28. Anagnostou A, Liu Z, Steiner M et al. Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci USA 1994; 91: 3974-3978
29. Masuda S, Nagao M, Takahata K et al. Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells. J Biol Chem 1993; 268: 11208-11216
30. D'Andrea AD, Lodish HF, Wong GG. Expression cloning of the murine erythropoietin receptor. Cell 1989; 57: 277-285
31. Mayeux P, Lacombe C, Casadevall N, Chretien S, Dusanter I, Gisselbrecht S. Structure of the murine erythropoietin receptor complex. Characterization of the erythropoietin cross-linked proteins. J Biol Chem 1991; 266: 23380-23385
32. Quelle DE, Quelle FW, Wojchowski DM. Mutations in the WSAWSE and cytosolic domains of the erythropoietin receptor affect signal transduction and ligand binding and internaliz ation. Mol Cell Biol 1992; 12: 4553-4561
33. Gobert S, Porteu F, Pallu S et al. Tyrosine phosphorylation of the erythropoietin receptor: role for differentiation and mitogenic signal transduction. Blood 1995; 86: 598-606
34. Winkelmann JC, Ward J, Mayeux P, Lacombe C, Schimmenti L, Jenkins RB. A translocated erythropoietin receptor gene in a human erythroleukemia cell line (TF-1) expresses an abnormal transcript and a truncated protein. Blood 1995; 85: 179-185
35. Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci USA 1990; 87: 6934-6938
36. Yoshimura A, Zimmers T, Neumann D, Longmore G, Yoshimura Y, Lodish HF. Mutations in the Trp-Ser-X-Trp-Ser motif of the erythropoietin receptor abolish processing, ligand binding, and activation of the receptor. J Biol Chem 1992; 267: 11619-11625
37. Hilton DJ, Watowich SS, Katz L, Lodish HF. Saturation mutagenesis of the WSXWS motif of the erythropoietin receptor. J Biol Chem 1996; 271: 4699-4708
38. Philo JS, Aoki KH, Arakawa T, Nahri LO, Wen J. Dimerization of the extracellular domain of the erythropoietin (Epo) receptor by Epo: one high-affinity and one low-affinity interaction. Biochemistry 1996; 35: 1681-1691
39. Qiu H, Belanger A, Yoon HW, Bunn HF. Homodimerization restores biological activity to an inactive erythropoietin mutant. J Biol Chem 1998; 273: 11173-11176
40. Elliott S, Lorenzini T, Yanagihara D, Chang D, Elliott G. Activation of the erythropoietin (Epo) receptor by bivalent anti-Epo receptor antibodies. J Biol Chem 1996; 271: 24691-24697
41. Schneider H, Chaovapong W, Matthews DJ et al. Homodimerization of the erythropoietin receptor by a divalent monoclonal antibody triggers cell proliferation and differentiation of erythroid precursors. Blood 1997; 89: 473-482
42. Wrighton NC, Farrell FX, Chang R et al. Small peptides as potent mimetics of the protein hormone erythropoietin. Science 1996; 273: 458-464
43. Livnah O, Stura EA, Johnson DL et al. Functional mimicry of a protein hormone by a peptide agonist: the EPO receptor complex at 2.8 Ȧ. Science 1996; 273: 464-471
44. Wrighton NC, Balasubramanian P, Barbone FP et al. Increased potency of an erythropoietin peptide mimetic through covalent dimerization. Nature Biotechnol 1997; 15: 1261-1265
45. Yoshimura A, Longmore G, Lodish HF. Point mutation in the exoplasmic domain of the erythropoietin receptor resulting in hormone-independent activation and tumorigenicity. Nature 1990; 348: 647-649
46. Longmore GD, Lodish HF. An activating mutation in the murine erythropoietin receptor induces erythroleukemia in mice: a cytokine receptor superfamily oncogene. Cell 1991; 67: 1089-1102
47. Longmore GD, Pharr PN, Lodish HF. A constitutively activated erythropoietin receptor stimulates proliferation and contributes to transformation of multipotent, committed nonerythroid and erythroid progenitor cells. Mol Cell Biol 1994; 14:2266-2277
48. Watowich SS, Yoshimura A, Longmore GD, Hilton DJ, Yoshimura Y, Lodish HF. Homodimerization and constutive activation of the erythropoietin receptor. Proc Natl Acad Sci USA 1992; 89: 2140-2144
49. Watowich SS, Hilton DJ, Lodish HF. Activation and inhibition of erythropoietin receptor function: role of receptor dimerization. Mol Cell Biol 1994; 14: 3535-3549
50. Witthuhn B, Quelle FW, Silvennoinen O et al. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following Epo stimulation. Cell 1993; 74: 227-236
51. Hilton CJ, Berridge MV. Conserved region of the cytoplasmic domain is not essential for erythropoietin-dependent growth. Growth Factors 1995; 121: 263-276
52. Damen J, Mui ALF, Hughes P, Humphries KR, Krystal G. Erythropoietin-induced tyrosine phosphorylation in a high erythropoietin-receptor expressing lymphoid cell line. Blood 1992; 80: 1923-1932
53. Dusanter-Fourt I, Casadevall N, Lacombe C et al. Erythropoietin induces the tyrosine phosphorylation of its own receptor in human erythropoietin-responsive cells. J Biol Chem 1992; 267: 10670-10675
54. Yoshimura A, Lodish HF. In vitro phosphorylation of the erythropoietin receptor and an associated protein, pp130. Mol Cell Biol 1992; 12: 706-715
55. Gobert S, Duprez V, Lacombe C, Gisselbrecht S, Mayeux P. Erythropoietin activates three forms of MAP kinase in UT7 erythroleukemia cells. Eur J Biochem 1995; 234: 75-83
56. Miura Y, Muira O, Ihle JN, Aoki N. Activation of the mitogen-activated protein kinase pathway by the erythropoietin receptor. J Biol Chem 1994; 269: 29962-29969
57. Carroll MP, Spivak JL, McMahon M, Weich N, Rapp UR, May WS. Erythropoietin induces Raf-1 activation and Raf-1 is required for erythropoietin-mediated proliferation. J Biol Chem 1991; 266: 14964-14969
58. Damen JE, Mui ALF, Puil L, Pawson T, Krystal G. Phosphatidylinositol 3-kinase associates, via its Src homology 2 domains, with the activated erythropoietin receptor. Blood 1993; 81: 3204-3210
59. He TC, Zhuang H, Jiang N, Waterfield MD, Wojchowski DM. Association of the p85 regulatory subunit of phosphatidylinositol 3-kinase with an essential erythropoietin receptor subdomain. Blood 1993; 82: 3530-3538
60. Mayeux P, Dusanter-Fourt I, Muller O et al. Erythropoietin induces the association of phosphatidylinositol 3′ kinase with a tyrosine phosphorylated complex containing the erythropoielin receptor. Eur J Biochem 1993; 216: 821-828
61. Miura O, Nakamura N, Ihle JN, Aoki N. Erythropoietin-dependent association of phosphatidylinositol 3-kinase with tyrosine-phosphorylated erythropoietin receptor. J Biol Chem 1994; 269: 614-620
62. Damen J, Cutler RL, Jiao H, Yi T, Krystal G. Phosphorylation of tyrosine 503 in the erythropoietin receptor (EpR) is essential for binding the p85 subunit of phosphatidylinositol (PI) 3-kinase and for EpR-associated PI 3-kinase activity. J Biol Chem 1995; 270: 23402-23406
63. Verdier F, Chrétien S, Billat C, Gisselbrecht S, Lacombe C, Mayeux P. Erythropoietin induces the tyrosine phosphorylation of insulin receptor substrate-2: an alternate pathway for erythropoietin-induced phosphatidylinositol 3-kinase activation. J Biol Chem 1997; 272: 26173-26178
64. Ihle JN. Cytokine receptor signalling. Nature 1995; 377: 591-594
65. Gouilleux F, Pallard C, Dusanter-Fourt I et al. Prolactin, growth hormone, erythropoietin and granulocyte-macrophage colony stimulating factor induce MGF-STAT5 DNA binding activity. EMBO J 1995; 14: 2005-2013
66. Pallard C, Fabrice G, Martine C, Groner B, Gisselbrecht S, Dusanter-Fourt I. Interleukin-3, erythropoietin, and prolactin activate a STAT5 like factor in lymphoid cells. J Biol Chem 1995; 270: 15942-15945
67. Wakao H, Harada N, Kitamura T, Mui ALF, Miyajima A. Interleukin 2 and erythropoietin activate STAT5/MGF via distinct pathways. EMBO J 1995; 14: 2527-2535
68. Damen JE, Wakao H, Miyajima A et al. Tyrosine 343 in the erythropoietin-receptor positively regulates erythropoietin-induced cell proliferation and STAT5 activation. EMBO J 1995; 14: 5557-5568
69. Gobert S, Chrétien S, Gouilleux F et al. Identification of tyrosine residues within the intracellular domain of the erythropoietin receptor crucial for STAT5 activation. EMBO J 1996; 15: 2434-2441
70. Chin H, Nakamura N, Kamiyama R, Miyasaka N, Ihle JN, Miura O. Physical and functional interactions between Stat5 and the tyrosine-phosphorylated receptors for erythropoietin and interleukin-3. Blood 1996; 88: 4415-4425
71. Klingmuller U, Bergelson S, Hsiao JG, Lodish HC. Multiple tyrosine residues in the cytosolic domain of the erythropoietin receptor promote activation of STAT5. Proc Natl Acad Sci USA 1996; 93: 8324-8328
72. Quelle FW, Wang D, Nosaka et al. Erythropoietin induces the activation of STAT5 through association with specific tyrosines on the receptor that are not required for a mitogenic response. Mol Cell Biol 1996; 16: 1622-1631
73. Chrétien S, Varlet P, Verdier F et al. Erythropoietin-induced differentiation of the human erythroleukemia cell line TF-1 correlates with impaired STAT5 activation. EMBO J 1996; 15: 4174-4181
74. Iwatsuki K, Endo T, Misawa H et al. STAT5 activation correlates with erythropoietin receptor-mediated erythroid differentiation of an erythroleukemia cell line. J Biol Chem 1997; 272: 8149-8152
75. Wakao H, Chida D, Damen JE, Krystal G, Miyajima A. A possible involvement of Stat5 in erythropoietin-induced hemoglobin synthesis. Biochem Biophys Res Commun 1997; 234: 198-205
76. Tauchi T, Damen JE, Toyama K, Feng GS, Broxmeyer HE, Krystal G. Tyrosine 426 within the activated erythropoietin receptor binds Syp, reduces the erythropoietin required for Syp tyrosine phosphorylation and promotes mitogenesis. Blood 1996; 87: 4495-4501
77. Klingmuller U, Lorenz U, Cantley LC, Neel BC, Lodish HC. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 1995; 80: 729-738
78. De La Chapelle A, Traskelin A, Juvonen E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proc Natl Acad Sci USA 1993; 90: 4495-4499
79. Krosl J, Damen J, Krystal G, Humphries RK. Interleukin-3 (IL-3) inhibits erythropoietin-induced differentiation in Ba/F3 cells via the IL-3 receptor alpha subunit. J Biol Chem 1996; 271: 27432-27437
80. Klingmuller U, Wu H, Hsiao JG et al. Identification of a novel pathway important for proliferation and differentiation of primary erythroid progenitors. Proc Natl Acad Sci USA 1997; 94: 3016-3021
81. Wu H, Klingmuller U, Acurio A, Hsiao JG, Lodish HF. Functional interaction of erythropoietin and stem cell factor receptors is essential for erythroid colony formation. Proc Natl Acad Sci USA 1997; 94: 1806-1810
82. Longmore GD, You Y, Molden J et al. Redundant and selective roles for erythropoietin receptor tyrosines in erythropoiesis in vivo. Blood 1998; 91: 870-878
83. Wu H, Klingmuller U, Besmer P, Lodish HF. Interaction of the erythropoietin and stem-cell-factor receptors. Nature 1995; 377: 242-246
84. Jacobs-Helber SM, Penta K, Sun Z, Lawson A, Sawyer ST. Distinct signaling from stem cell factor and erythropoietin in HCD57 cells. J Biol Chem 1997; 272: 6850-6853
85. Schuster SJ, Badiavas EV, Costa-Giomi P, Weinmann R, Erslev AJ, Caro J. Stimulation of erythropoietin gene transcription during hypoxia and cobalt exposure. Blood 1989; 73: 13-16
86. Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE. Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. Proc Natl Acad Sci USA 1991; 88: 5680-5684
87. Beck I, Ramirez S, Weinmann R, Caro J. Enhancer element at the 3′-flanking region controls transcriptional response to hypoxia in the human erythropoietin gene. J Biol Chem 1991; 266: 15563-15566
88. Blanchard KL, Acquaviva AM, Galson DL, Bunn HF. Hypoxic induction of the human erythropoietin gene: cooperation between the promoter and enhancer, each of which contains steroid receptor response elements. Mol Cell Biol 1992; 12: 5373-5385
89. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992; 12: 5447-5454
90. Beck I, Weinmann R, Caro J. Characterization of hypoxia-responsive enhancer in the human erythropoietin gene shows presence of hypoxia-inducible 120-Kd nuclear DNA-binding protein in erythropoietin-producing and nonproducing cells. Blood 1993; 82: 704-711
91. Wang GL, Semenza GL. Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem 1993; 268: 21513-21518
92. Pugh CW, Ebert BL, Ebrahim O, Ratcliffe PJ. Characterisation of functional domains within the mouse erythropoietin 3′ enhancer conveying oxygen-regulated responses in different cell lines. Biochim Biophys Acta 1994; 1217: 297-306
93. Galson DL, Tsuchiya T, Tendler DS et al. The orphan receptor hepatic nuclear factor 4 functions as a transcriptional activator for tissue-specific and hypoxia-specific erythropoietin gene expression and is antagonized by EAR3/COUP-TF1. Mol Cell Biol 1995; 15: 2135-2144
94. Arany Z, Huang LE, Eckner R et al. An essential role for p300/CBP in the cellular response to hypoxia. Proc Natl Acad Sci USA 1996; 93: 12969-12973
95. Huang LE, Ho V, Arany Z et al. Erythropoietin gene regulation depends on heme-dependent oxygen sensing and assembly of interacting transcription factors. Kidney Int 1997; 51: 548-552
96. 2 tension. Proc Natl Acad Sci USA 1995; 92: 5510-5514
97. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 1995; 270: 1230-1237
98. Hoffman EC, Reyes H, Chu FF et al. Cloning of a factor required for activity of the Ah (dioxin) receptor. Science 1991; 252: 954-958
99. Kallio PJ, Pongratz I, Gradin K, McGuire J, Poellinger L. Activation of hypoxia-inducible factor 1alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proc Natl Acad Sci USA 1997; 94: 5667-5672
100. Salceda S, Caro J. Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 1997; 272: 22642-22647
101. Maxwell PH, Pugh CW, Ratcliffe PJ. Inducible operation of the erythropoietin 3′ enhancer in multiple cell lines: evidence for a widespread oxygen-sensing mechanism. Proc Natl Acad Sci USA 1993; 90: 2423-2427
102. Wang GL, Semenza GL. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 1993; 90: 4304-4308
103. Wenger RH, Gassmann M. Oxygen(es) and the hypoxia-inducible factor-1. Biol Chem 1997; 378: 609-616
104. Bunn HF, Poyton RO. Oxygen sensing and molecular adaptation to hypoxia. Physiol Rev 1996; 76: 839-885
105. Porter DL, Goldberg MA. Physiology of erythropoietin production. Semin Hematol 1994; 31: 112-121
106. Goldberg MA, Dunning SP, Bunn HF. Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. Science 1988; 242: 1412-1415
107. Faquin WC, Schneider TJ, Goldberg MA. Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Blood 1992; 79: 1987-1994
108. Means RT, Jr, Krantz SB. Progress in understanding the pathogenesis of the anemia of chronic disease. Blood 1992; 80: 1639-1647
109. Taniguchi S, Dai CH, Price JO, Krantz SB. Interferon gamma downregulates stem cell factor and erythropoietin receptors but not insulin-like growth factor-I receptors in human erythroid colony-forming cells. Blood 1997; 90: 2244-2252
110. Dai C-H, Price JO, Brunner T, Krantz SB. Fas ligand is present in human erythroid colony-forming cells and interacts with Fas induced by interferon γ to produce erythroid cell apoptosis. Blood 1998; 91: 2135-2142