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Cytokine control of developmental programs in normal hematopoiesis and leukemia

Oncogene volume 21, pages 3284–3294 (2002)Cite this article

Abstract

The establishment of a system for in vitro clonal development of hematopoietic cells made it possible to discover the cytokines that regulate hematopoiesis. These cytokines include colony stimulating factors and others, which interact in a network, and there is a cytokine cascade which couples growth and differentiation. A network allows considerable flexibility and a ready amplification of response to a particular stimulus. A network may also be necessary to stabilize the whole system. Cells called hematopoietic stem cells (HSC) can repopulate all hematopoietic lineages in lethally irradiated hosts, and under appropriate conditions give rise to neuronal, muscle, and epithelial cells. Granulocyte colony stimulating factor induces migration of both HSC and in vitro colony forming cells from the bone marrow to peripheral blood. Granulocyte colony stimulating factor is also used clinically to repair irradiation and chemotherapy associated suppression of normal hematopoiesis in cancer patients, and to stimulate normal granulocyte develpment in patients with infantile congenital agranulocytosis. It is suggested that there may also be appropriate conditions under which in vitro colony forming cells have a wider differentiation potential similar to that shown by HSC. An essential part of the developmental program is cytokine suppression of apoptosis by changing the balance in expression of apoptosis inducing and suppressing genes. Decreasing the level of cytokines that suppress therapeutic induction of apoptosis in malignant cells can improve cancer therapy. Cytokines and some other compounds can reprogram abnormal developmental programs in leukemia, so that the leukemic cells differentiate to mature non dividing cells, and this can also be used for therapy. There is considerable plasticity in the developmental programs of normal and malignant cells.

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References

  • Abrahamson JLA, Lee JM, Bernstein A . 1995 Mol. Cell. Biol. 15: 6953–6960

  • Agoff SN, Hou J, Linzer DIH, Wu B . 1993 Science 259: 84–87

  • Alison MR, Poulsom R, Jeffery R, Dhillon AP, Quaglia A, Jacob J, Novelli M, Prentice G, Williamson J, Wright NA . 2000 Nature 406: 257–

  • Amanullah A, Hoffman B, Liebermann DA . 2000 Blood 96: 475–482

  • Asher G, Lotem J, Cohen B, Sachs L, Shaul Y . 2001 Proc. Natl. Acad. Sci. USA 98: 1188–1193

  • Attardi LD, Reczek EE, Cosmas C, Demicco EG, McCurrach ME, Lowe SW, Jacks T . 2000 Genes Dev. 14: 704–718

  • Bataille R, Barlogie B, Lu ZY, Rossi J-F, Lavabre-Bertrand T, Beck T, Wijdenes J, Brochier J, Klein B . 1995 Blood 86: 685–691

  • Bjornson CRR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL . 1999 Science 283: 534–537

  • Blatt C, Lotem J, Sachs L . 1992 Cell Growth Differ. 3: 671–676

  • Bonifer C, Faust N, Geiger H, Müller AM . 1998 Immunol. Today 19: 236–241

  • Bradley TR, Metcalf D . 1966 Aust. J. Exper. Biol. Med. Sci. 44: 287–299

  • Canman CE, Gilmer TM, Coutts SB, Kastan MB . 1995 Genes Dev. 9: 600–601

  • Carter BZ, Miella M, Altieri DC, Andreeff M . 2001 Blood 97: 2784–2790

  • Chao J-R, Wang J-M, Lee S-F, Peng H-W, Lim Y-H, Chou C-H, Li J-C, Huang H-M, Chou C-K, Kuo M-L, Yen JJ-Y, Yang-Yen H-F . 1998 Mol. Cell. Biol. 18: 4883–4898

  • Chauhan D, Hideshima T, Rosen S, Reed JC, Kharbanda S, Anderson KC . 2001 J. Biol. Chem. 276: 24453–24456

  • Chauhan D, Kharbanda S, Ogata A, Urashima M, Teoh G, Robertson M, Kufe DW, Anderson KC . 1997 Blood 89: 227–234

  • Clark SC, Kamen R . 1987 Science 236: 1129–1237

  • Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, Wyllie AH . 1993 Nature 362: 849–852

  • Cohen L, Sachs L . 1981 Proc. Natl. Acad. Sci. USA 78: 353–357

  • Collins MKL, Marvel J, Malde P, Lopez-Rivas A . 1992 J. Exp. Med. 176: 1043–1051

  • Datta SR, Brunet A, Greenberg ME . 1999 Genes Dev. 13: 2905–2927

  • Degos L . 1992 Int. J. Cell Cloning 10: 63–69

  • Deveraux QL, Reed JC . 1999 Genes Dev. 13: 239–252

  • Digicaylioglu M, Lipton SA . 2001 Nature 412: 641–647

  • Dijkers PF, Medema RH, Lammers J-WJ, Koenderman L, Coffer PJ . 2000 Curr. Biol. 10: 1201–1204

  • Dong F, van Buitenen C, Pouwels K, Hoefsloot LH, Löwenberg B, Touw IP . 1993 Mol. Cell. Biol. 13: 7774–7781

  • D'Souza S, Xin H, Walter S, Choubey D . 2001 J. Biol. Chem. 276: 298–305

  • Dzierzak E, Medvinsky A, de Bruijn M . 1998 Immunol. Today 19: 228–236

  • Eglitis MA, Mezey E . 1997 Proc. Natl. Acad. Sci. USA 94: 4080–4085

  • Fearon ER, Burke PJ, Schiffer CA, Zehnbauer BA, Vogelstein B . 1986 N. Eng. J. Med. 315: 15–24

  • Ferrari G, Cusella-DeAngelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, Mavilio F . 1998 Science 279: 1528–1530

  • Fibach E, Landau T, Sachs L . 1972 Nature New Biol. 237: 276–278

  • Fibach E, Hayashi M, Sachs L . 1973 Proc. Natl. Acad. Sci. USA 70: 343–346

  • Fibach E, Sachs L . 1976 J. Cell. Physiol. 89: 259–266

  • Fukunaga R, Ishizaka-Ikeda E, Nagata S . 1993 Cell 74: 1079–1087

  • Gazitt Y . 2001 J. Hematother. Stem Cell Res. 10: 229–236

  • Gerassi E, Sachs L . 1976 Proc. Natl. Acad. Sci. USA 73: 4546–4550

  • Ginsburg H, Sachs L . 1963 J. Natl. Cancer Inst. 31: 1–40

  • Gonda TJ, Metcalf D . 1984 Nature 310: 249–251

  • Gootwine E, Webb CG, Sachs L . 1982 Nature 299: 63–65

  • Griffin JD, Löwenberg B . 1986 Blood 68: 1185–1195

  • Gross A, Jockel J, Wei MC, Korsmeyer SJ . 1998 EMBO J. 17: 3878–3885

  • Gurdon JB, Colman A . 1999 Nature 402: 743–746

  • Haupt Y, Maya R, Kazaz A, Oren M . 1997 Nature 387: 296–299

  • Hoffman-Liebermann B, Liebermann DA . 1991 Mol. Cell Biol. 11: 2375–2381

  • Hoffman-Liebermann B, Liebermann D, Sachs L . 1981 Dev. Biol. 81: 255–265

  • Horsfall MJ, Hui CH, To LB, Begley CG, Basser RL, Simmons PJ . 2000 Br. J. Haematol. 109: 751–758

  • Hültner L, Szöts H, Van Snick J, Moeller J, Welle M, Dörmer P . 1989 Growth Factors 2: 43–51

  • Ichikawa Y, Pluznik DH, Sachs L . 1966 Proc. Natl. Acad. Sci. USA 56: 488–495

  • Ichikawa Y, Pluznik DH, Sachs L . 1967 Proc. Natl. Acad. Sci. USA 58: 1480–1486

  • Ihle JN . 1995 Nature 377: 591–594

  • Ihle JN, Keller J, Henderson L, Klein F, Palaszinski E . 1982 J. Immunol. 129: 2431–2436

  • Jackson KA, Mi T, Goodell MA . 1999 Proc. Natl. Acad. Sci. USA 96: 14482–14486

  • Jacobsen SEW, Ruscetti FW, Dubois CM, Lee J, Boone TC, Keller JR . 1991 Blood 77: 1706–1716

  • Kannan K, Kaminski N, Rechavi G, Jacob-Hirsch J, Amariglio N, Givol D . 2001 Oncogene 20: 3449–3455

  • Kaplinsky C, Lotem J, Sachs L . 1996 Leukemia 10: 460–465

  • Kaushansky K . 1995 Blood 86: 419–431

  • Kennedy M, Firpo M, Choi K, Wall C, Robertson S, Kabrun N, Keller G . 1997 Nature 386: 488–493

  • Khaled AR, Kim K, Hofmeister R, Muegge K, Durum SK . 1999 Proc. Natl. Acad. Sci. USA 96: 14476–14481

  • Kishimoto T, Taga T, Akira S . 1994 Cell 76: 253–262

  • Ko LJ, Prives C . 1996 Genes Dev. 10: 1054–1072

  • Korsmeyer SJ . 1992 Blood 80: 879–886

  • Kovalovich K, Li W, DeAngelis R, Greenbaum LE, Ciliberto G, Taub R . 2001 J. Biol. Chem. 276: 26605–26613

  • Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, Neutzel S, Sharkis SJ . 2001 Cell 105: 369–377

  • Kubbutat MH, Jones SN, Vousden KH . 1997 Nature 387: 299–303

  • Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dhose M, Osborne L, Wang X, Finegold M, Weissman IL, Grompe M . 2000 Nat. Med. 6: 1229–1234

  • Landau T, Sachs L . 1971 Proc. Natl. Acad. Sci. USA 68: 2540–2544

  • Levine AJ . 1997 Cell 88: 323–331

  • Liebermann D, Hoffman-Liebermann B, Sachs L . 1980 Dev. Biol. 79: 46–63

  • Lin EY, Orlofsky A, Berger MS, Przystowsky MB . 1993 J. Immunol. 151: 1979–1988

  • Lin Y, Ma W, Benchimol S . 2000 Nat. Gen. 26: 122–127

  • Lindsten T, Ross AJ, King A, Zong W-X, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar P, Frauwirth K, Chen Y, Wei M, Eng VM, Adelman DM, Simon MC, Ma A, Golden JA, Evan G, Korsmeyer SJ, MacGregor GR, Thompson CB . 2000 Mol. Cell 6: 1389–1399

  • Lotem J, Cragoe EJ, Sachs L . 1991a Blood 78: 953–960

  • Lotem J, Peled-Kamar M, Groner Y, Sachs L . 1996 Proc. Natl. Acad. Sci. USA 93: 9166–9171

  • Lotem J, Sachs L . 1974 Proc. Natl. Acad. Sci. USA 71: 3507–3511

  • Lotem J, Sachs L . 1977 Proc. Natl. Acad. Sci. USA 74: 5554–5558

  • Lotem J, Sachs L . 1978 Proc. Natl. Acad. Sci. USA 75: 3781–3785

  • Lotem J, Sachs L . 1981 Int. J. Cancer 28: 375–386

  • Lotem J, Sachs L . 1982 Proc. Natl. Acad. Sci. USA 79: 4347–4351

  • Lotem J, Sachs L . 1983 Int. J. Cancer 32: 127–134

  • Lotem J, Sachs L . 1984 Int. J. Cancer 33: 147–154

  • Lotem J, Sachs L . 1986 EMBO J. 5: 2163–2170

  • Lotem J, Sachs L . 1987 Int. J. Cancer 40: 532–539

  • Lotem J, Sachs L . 1988 Blood 71: 375–382

  • Lotem J, Sachs L . 1989a Leukemia Res. 13: 13–21

  • Lotem J, Sachs L . 1989b Blood 74: 579–585

  • Lotem J, Sachs L . 1990 Blood 76: 1315–1322

  • Lotem J, Sachs L . 1992a Leukemia 6: 426–431

  • Lotem J, Sachs L . 1992b Blood 80: 1750–1757

  • Lotem J, Sachs L . 1993a Blood 82: 1092–1096

  • Lotem J, Sachs L . 1993b Cell Growth Differ. 4: 41–47

  • Lotem J, Sachs L . 1995a Leukemia 9: 685–692

  • Lotem J, Sachs L . 1995b Proc. Natl. Acad. Sci. USA 92: 9672–9676

  • Lotem J, Sachs L . 1996a Proc. Natl. Acad. Sci. USA 93: 12507–12512

  • Lotem J, Sachs L . 1996b Leukemia 10: 925–931

  • Lotem J, Sachs L . 1997 Proc. Natl. Acad. Sci. USA 94: 9349–9353

  • Lotem J, Sachs L . 1998 Proc. Natl. Acad. Sci. USA 95: 4601–4606

  • Lotem J, Sachs L . 1999 Apoptosis 4: 187–196

  • Lotem J, Shabo Y, Sachs L . 1991b Cell Growth Differ. 2: 421–427

  • Lotem J, Sachs L . 2002 Sem. Cancer Biol. in press

  • Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T . 1993 Nature 362: 847–849

  • Lyman SD, James L, VandenBos T, de Vries P, Brasel K, Gliniak B, Hollingsworth LT, Picha KS, McKenna HJ, Splett RR, Fletcher FF, Maraskovsky E, Farrah F, Foxworthe D, Williams DE, Beckmann MP . 1993 Cell 75: 1157–1167

  • Masuda A, Matsuguchi T, Yamaki K, Hayakawa T, Yoshikai Y . 2001 J. Biol. Chem. 276: 26107–26113

  • Melamed D, Tiefenbrun N, Yarden A, Kimchi A . 1993 Mol. Cell. Biol. 13: 5255–5265

  • Metcalf D . 1985 Science 229: 16–22

  • Metcalf D, Nossal GJV, Warner NL, Miller JFAP, Mandel TE, Layton JE, Gutman GA . 1975 J. Exp. Med. 142: 1534–1549

  • Moroni MC, Hickman ES, Denchi EL, Caprara G, Colli E, Cecconi F, Müller H, Hellin K . 2001 Nat. Cell Biol. 3: 552–558

  • Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, Aono A, Nishimoto N, Kajita T, Taga T, Yoshizaki K, Akira S, Kishimoto T . 1997 Nature 387: 924–929

  • Nakano K, Vousden KH . 2001 Mol. Cell 7: 683–694

  • Oda K, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N . 2000a Science 288: 1053–1058

  • Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T, Nishimori H, Tamai K, Tokino T, Nakamura Y, Taya Y . 2000b Cell 102: 849–862

  • Okamura S, Arakawa H, Tanaka T, Nakanishi H, Ng CC, Taya Y, Monden M, Nakamura Y . 2001 Mol. Cell 8: 85–94

  • Oren M . 1992 FASEB J. 6: 3169–3176

  • Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P . 2001 Nature 410: 701–705

  • Paran M, Sachs L . 1969 J. Cell. Physiol. 73: 91–92

  • Paran M, Sachs L, Barak Y, Resnitzky P . 1970 Proc. Natl. Acad. Sci. USA 67: 1542–1549

  • Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, Boggs SS, Greenberger JS, Goff JP . 1999 Science 284: 1168–1170

  • Pike BL, Robinson WA . 1970 J. Cell. Physiol. 76: 77–84

  • Pluznik DH, Sachs L . 1965 J. Cell Comp. Physiol. 66: 319–324

  • Pluznik DH, Sachs L . 1966 Exp. Cell. Res. 43: 553–563

  • Prisco M, Hongo A, Rizzo MG, Sacchi A, Baserga R . 1997 Mol. Cell. Biol. 17: 1084–1092

  • Puthier D, Bataille R, Amiot M . 1999 Eur. J. Immunol. 29: 3945–3950

  • Renné C, Kallen K-J, Müllberg J, Jostock T, Grötzinger J, Rose-John S . 1998 J. Biol. Chem. 273: 27213–27219

  • Sachs L . 1978 Nature 274: 535–539

  • Sachs L . 1980 Proc. Natl. Acad. Sci. USA 77: 6152–6156

  • Sachs L . 1982 Cancer Surv. 1: 321–342

  • Sachs L . 1986 Scient. Amer. 254: 40–47

  • Sachs L . 1987a Proc. R. Soc. Lond. B Biol. Sci. 231: 289–312

  • Sachs L . 1987b Science 238: 1374–1379

  • Sachs L . 1990 Cancer 65: 2196–2206

  • Sachs L . 1995 Adv. Cancer Res. 66: 1–40

  • Sachs L . 1996 Proc. Natl. Acad. Sci. USA 93: 4742–4749

  • Sachs L, Lotem J . 1993 Blood 82: 15–21

  • Sanz C, Benito A, Inohara N, Ekhterae D, Nunez G, Fernandez-Luna JL . 2000 Blood 95: 2742–2747

  • Sanz C, Mellstrom B, Link WA, Naranjo JR, Fernandez-Luna JL . 2001 EMBO J. 20: 2286–2292

  • Selvakumaran M, Liebermann DA, Hoffman-Liebermann B . 1992 Mol. Cell. Biol. 12: 2493–2500

  • Schneider E, Ploemacher RE, Navarro S, Van Beurden C, Dy M . 1991 Blood 78: 329–338

  • Shabo Y, Lotem J, Rubinstein M, Revel M, Clark SC, Wolf SF, Kamen R, Sachs L . 1988 Blood 72: 2070–2073

  • Shabo Y, Lotem J, Sachs L . 1989a Mol. Cell. Biol. 9: 4109–4112

  • Shabo Y, Lotem J, Sachs L . 1989b Leukemia 3: 859–865

  • Shaw P, Bovey R, Tardy S, Sahli R, Sordat B, Costa J . 1992 Proc. Natl. Acad. Sci. USA 89: 4495–4499

  • Shinjyo T, Kuribara R, Inukai T, Hosoi H, Kinoshita T, Miyajima A, Houghton PJ, Look AT, Ozawa K, Inaba T . 2001 Mol. Cell. Biol. 21: 854–864

  • Sieweke MH, Graf T . 1998 Curr. Opin. Gen. Dev. 8: 545–551

  • Starr R, Willson TA, Viney EM, Murray LJL, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ . 1997 Nature 387: 917–921

  • Stephenson JR, Axelrad AA, McLeod DL, Shreeve MM . 1971 Proc. Natl. Acad. Sci. USA 68: 1542–1546

  • Strasser A, Harris AW, Jacks T, Cory S . 1994 Cell 79: 329–339

  • Symonds G, Sachs L . 1983 EMBO J. 2: 663–667

  • Taga T, Kishimoto T . 1997 Annu. Rev. Immunol. 15: 797–819

  • Tanaka H, Matsumura I, Nakajima K, Daino H, Sonoyama J, Yoshida H, Oritani K, Machii T, Yamamoto M, Hirano T, Kanakura Y . 2000 Blood 95: 1264–1273

  • Taniguchi T . 1995 Science 268: 251–255

  • Tanuma N, Nakamura K, Shima H, Kikuchi K . 2000 J. Biol. Chem. 275: 28216–28221

  • Tenen DG, Hromas R, Licht JD, Zhang DE . 1997 Blood 90: 489–519

  • Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, Henegariu O, Krause DS . 2000 Hepatology 32: 11–16

  • Thompson CB . 1995 Science 267: 1456–1462

  • Vander Heiden MG, Chandel NS, Li XX, Schumacker PT, Colombini M, Thompson CB . 2000 Proc. Natl. Acad. Sci. USA 97: 4666–4671

  • Vander Heiden MG, Chandel NS, Schumacker PT, Thompson CB . 1999 Mol. Cell 3: 159–167

  • Vander Heiden MG, Li XX, Gottlieb E, Hill RB, Thompson CB, Colombini M . 2001 J. Biol. Chem. 276: 19414–19419

  • Vogelstein B, Lane D, Levine AJ . 2000 Nature 408: 307–310

  • Webb CG, Gootwine E, Sachs L . 1984 Dev. Biol. 101: 221–224

  • Wei MC, Zong W-X, Cheng EH-Y, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ . 2001 Science 292: 727–730

  • Weissman IL . 2000 Cell 100: 157–168

  • Welniak LA, Khaled AR, Anver MR, Komschlies KL, Wiltrout RH, Durum S, Ruscetti FR, Blazar BR, Murphy WJ . 2001 J. Immunol. 166: 2924–2938

  • Witte ON . 1990 Cell 63: 5–6

  • Yonish-Rouach E, Reznitzky D, Lotem J, Sachs L, Kimchi A, Oren M . 1991 Nature 352: 345–347

  • Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B . 2001 Mol. Cell 7: 673–682

  • Zhang XG, Gu JJ, Lu ZY, Yasukawa K, Yancopoulos GD, Turner K, Shoyab M, Taga T, Kishimoto T, Bataille R, Klein B . 1994 J. Exp. Med. 179: 1337–1342

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Acknowledgements

This work was supported by a research grant from the Dolfi and Lola Ebner Center for Biomedical Research.

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    Joseph Lotem & Leo Sachs

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Lotem, J., Sachs, L. Cytokine control of developmental programs in normal hematopoiesis and leukemia. Oncogene 21, 3284–3294 (2002). https://doi.org/10.1038/sj.onc.1205319

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