Thromb Haemost 1999; 82(02): 312-317
DOI: 10.1055/s-0037-1615848
Research Article
Schattauer GmbH

Thrombopoietin: From Theory to Reality

Kenneth Kaushansky
1   Division of Hematology, School of Medicine, University of Washington, Seattle, WA, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
09 December 2017 (online)

Introduction

The term thrombopoietin (TPO) was first penned in 1958 to describe the primary regulator of platelet production. Multiple efforts to purify the hormone were unsuccessful throughout the 1970s and 1980s because the protein was scarce and starting materials for purification biochemically complex. Even purification of thrombocytopenic plasma, which is the richest source of TPO, was unsuccessful.1,2 However, the cloning of the proto-oncogene c-mpl 3 opened an alternative route to the identification of TPO. Detailed study of the c-mpl gene revealed that it encoded an orphan hematopoietic cytokine receptor. Its tissue distribution and experiments designed to eliminate its expression suggested that c-mpl encoded the TPO receptor.4,5 In 1994, using three distinct strategies, five separate groups either purified protein or cloned cDNA for TPO.6 This review will focus on the physiology of TPO production and function, concentrating on recent findings that help to explain platelet homeostasis and how our understanding of TPO can translate into better patient care for thrombocytopenic patients.

 
  • References

  • 1 McDonald TP. Thrombopoietin: its biology, purification, and characterization. Exp Hematol. 1988; 16: 201-205.
  • 2 Hill RJ, Levin J. Regulators of thrombopoiesis: their biochemistry and physiology. Blood Cells. 1989; 15: 141-166.
  • 3 Vigon I, Mornon J-P, Cocault L, Mitjavila MT, Tambourin P, Gisselbrecht S, Souyri M. Molecular cloning and characterization of MPL, the human homolog of the v-mpl oncogene: identification of a member of the hematopoietic growth factor receptor superfamily. Proc Natl Acad Sci USA. 1992; 89: 5640-5644.
  • 4 Methia N, Louache F, Vainchenker W, Wendling F. Oligodeoxynucleotides antisense to the proto-oncogene c-mpl specifically inhibit in vitro megakaryocytopoiesis. Blood 1993; 82: 1395-1401.
  • 5 Skoda RC, Seldin DC, Chiang MK, Peichel CL, Vogt TF, Leder P. Murine c-mpl: a member of the hematopoietic growth factor receptor superfamily that transduces a proliferative signal. EMBO J. 1993; 12: 2645-2653.
  • 6 Kaushansky K. Thrombopoietin: the primary regulator of platelet production. Blood 1995; 86: 419-431.
  • 7 de Sauvage FJ, Hass PE, Spencer SD, Malloy BE, Gurney AL, Spencer SA, Darbonne WC, Henzel WJ, Wong SC, Kuang WJ. et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature 1994; 369: 533-538.
  • 8 Lok S, Kaushansky K, Holly RD, Kuijper JL, Lofton-Day CE, Oort PJ, Grant FJ, Heipel MD, Burkhead SK, Kramer JM. et al. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature 1994; 369: 565-568.
  • 9 Bartley TD, Bogenberger J, Hunt P, Li YS, Lu HS, Martin F, Change MS, Samal B, Nichol JL, Swift S. et al. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell. 1994; 77: 1117-1124.
  • 10 Sohma Y, Akahori H, Seki N, Hori T, Ogami K, Kato T, Shimada Y, Kawamura K, Miyazaki H. Molecular cloning and chromosomal localization of the human thrombopoietin gene. FEBS Lett. 1994; 353: 57-61.
  • 11 Kaushansky K, Karplus A. The hematopoietic growth factors: understanding functional diversity in structural terms. Blood 1993; 82: 3229-3240.
  • 12 Pearce KH, Potts BJ, Presta LG, Bald LN, Fendly BM, Wells JA. Mutational analysis of thrombopoietin for identification of receptor and neutralizing antibody sites. J Biol Chem. 1997; 272: 20595-20602.
  • 13 Park H, Park SS, Jin EH, Song JS, Ryu SE, Yu MH, Hong HJ. Identification of functionally important residues of human thrombopoietin. J Biol Chem. 1998; 273: 256-261.
  • 14 Foster DC, Sprecher CA, Grant FJ, Kramer JM, Kuijper JL, Holly RD, Whitmore TE, Heipel MD, Bell LA, Ching AF. et al. Human thrombopoietin: gene structure, cDNA sequence, expression and chromosomal localization. Proc Natl Acad Sci USA. 1994; 91: 13023.
  • 15 Bernstein R, Bagg A, Pinto M, Lewis D, Mendelow B. Chromosome 3q21 abnormalities associated with hyperactive thrombopoiesis in acute blastic transformation of chronic myeloid leukemia. Blood 1986; 68: 652-657.
  • 16 Hokum MM, Lacey D, Kintsler OB, Choi E, Kaufman S, Faust J, Rowan C, Dwyer E, Nichol JL, Grasel T. et al. Pegylated megakaryocyte growth and development factor abrogates the lethal thrombocytopenia associated with carboplatin and irradiation in mice. Blood 1995; 86: 4486-4492.
  • 17 Linden H, Kaushansky K. The glycan domain of thrombopoietin (TPO) functions alone in trans to enhance secretion of the receptor binding domain of TPO and other cytokines. Blood 1998; 92: 674a.
  • 18 Kaushansky K, Broudy VC, Lin N, Jorgensen MJ, McCarty J, Fox N, Zucker-Franklin D, Lofton-Day C. Thrombopoietin, the Mpl-ligand, is essential for full megakaryocyte development. Proc Natl Acad Sci USA. 1995; 92: 3234-3238.
  • 19 Komatsu N, Kirito K, Shimizu R, Kunitama M, Yamada M, Uchida M, Takatoku M, Eguchi M, Miura Y. In vitro development of erythroid and megakaryocytic cells from a UT-7 subline, UT-7/GM. Blood 1997; 89: 4021-4033.
  • 20 Kaushansky K, Lok S, Holly RD, Broudy VC, Lin N, Bailey MC, Forstrom JW, Buddle MM, Oort PJ, Hagen FS. et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature 1994; 369: 568-571.
  • 21 Zauli G, Bassini A, Vitale M, Gibellini D, Celeghini C, Caramelli E, Pierpaoli S, Guidotti L, Capitani S. Thrombopoietin enhances the αIIb β3-dependent adhesion of megakaryocytic cells to fibrinogen or fibronectin through PI 3 kinase. Blood 1997; 89: 883-895.
  • 22 Cramer EM, Norol F, Guichard J, Breton-Gorius J, Vainchenker W, Masse JM, Debili N. Ultrastructure of platelet formation by human megakaryocytes cultured with the Mpl ligand. Blood 1997; 89: 2336-2346.
  • 23 Nichol J, Hokom M, Hornkohl A, Sheridan WP, Ohashi H, Kato T, Li YS, Bartley TD, Choi E, Bogenberger J. et al. Megakaryocyte growth and development factor. Analysis of in vitro effects on human megakaryopoiesis and endogenous serum levels during chemotherapy induced thrombocytopenia. J Clin Invest. 1995; 95: 2973-2978.
  • 24 Broudy VC, Lin NL, Kaushansky K. Thrombopoietin (c-mpl ligand) acts synergistically with erythropoietin, stem cell factor, and IL-11 to enhance murine megakaryocyte colony growth and increases megakaryocyte ploidy in vitro. Blood 1995; 85: 1719-1726.
  • 25 Nagasawa T, Osada M, Komeno T. et al. In vitro and in vivo deprivation of thrombopoietin induces megakaryocytic apoptosis and regulates platelet production. Exp Hematol. 1997; 25: 897.
  • 26 Sitnicka E, Lin N, Priestley GV, Fox N, Broudy VC, Wolf NS, Kaushansky K. The effect of thrombopoietin on the proliferation and differentiation of murine hematopoietic stem cells. Blood 1996; 87: 4998-5005.
  • 27 Kobayashi M, Laver JH, Kato T, Miyazaki H, Ogawa M. Thrombopoietin supports proliferation of human primitive hematopoietic cells in synergy with steel factor and/or interleukin-3. Blood 1996; 88: 429-436.
  • 28 Alexander WS, Roberts AW, Nicola NA, Li R, Metcalf D. Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietin receptor c-Mpl. Blood 1996; 87: 2162-2170.
  • 29 Carver-Moore K, Broxmeyer HE, Luoh SM, Cooper S, Peng J, Burstein SA, Moore MW, de Sauvage FJ. Low levels of erythroid and myeloid progenitors in thrombopoietin and mpl-deficient mice. Blood 1996; 88: 803-808.
  • 30 Kimura S, Roberts AW, Metcalf D, Alexander WS. Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin. Proc Natl Acad Sci USA. 1998; 95: 1195-1200.
  • 31 Solar GP, Kerr WG, Zeigler FC, Hess D, Donahue C, de Sauvage FJ, Eaton DL. Role of c-mpl in early hematopoiesis. Blood 1998; 92: 4-10.
  • 32 McCarty JM, Sprugel KH, Fox NE, Sabath DE, Kaushansky K. Murine thrombopoietin mRNA levels are modulated by platelet count. Blood 1995; 86: 3668-3675.
  • 33 Kuter DJ, Rosenberg RD. The reciprocal relationship of thrombopoietin (c-Mpl Ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit. Blood 1995; 85: 2720-2730.
  • 34 Kosugi S, Kurata Y, Tomiyama Y, Tahara T, Kato T, Tadokoro S, Shiraga M, Honda S, Kanakura Y, Matsuzawa Y. Circulating thrombopoietin level in chronic immune thrombocytopenic purpura. Br J Hematol. 1996; 93: 704-706.
  • 35 Marsh JCW, Gibson FM, Prue RL, Bowen A, Dunn VT, Hornkohl AC, Nichol JL, Gordon-Smith EC. Serum thrombopoietin levels in patients with aplastic anemia. Br J Haematol. 1996; 95: 605-610.
  • 36 Emmons RVB, Reid DM, Cohen RL, Meng G, Young NS, Dunbar CE, Shulman NR. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood 1996; 87: 4068-4071.
  • 37 Ichikawa N, Ishida F, Shimodaira S, Tahara T, Kato T, Kitano K. Regulation of serum thrombopoietin levels by platelets and megakaryocytes in patients with aplastic anemia and idiopathic thrombocytopenic purpura. Thromb Haemost. 1996; 76: 156-160.
  • 38 Gernsheimer T, Stratton J, Ballem PJ, Slichter SJ. Mechanisms of response to treatment in autoimmune thrombocytopenic purpura. N Engl J Med. 1989; 320: 974-980.
  • 39 Cardier JE, Dempsey J. Thrombopoietin and its receptor, c-mpl, are constitutively expressed by mouse liver endothelial cells: evidence of thrombopoietin as a growth factor for liver endothelial cells. Blood 1998; 91: 923-929.
  • 40 Sotiropoulos D, Adamson JW. Mechanism of action of interleukin 11 (IL-11) on in vitro megakaryopoiesis. Exp Hematol. 1996; 24: 1069.
  • 41 Cerutti A, Custodi P, Duranti M, Noris P, Balduini CL. Thrombopoietin levels in patients with primary and reactive thrombocytosis. Br J Haematol. 1997; 99: 281-284.
  • 42 Peck-Radosavljevic M, Wichlas M, Pidlich J, Sims P, Meng G, Zacherl J, Garg S, Datz C, Gangl A, Ferenci P. Blunted thrombopoietin response to interferon α-induced thrombocytopenia during treatment for hepatitis C. Hepatology. 1998; 28: 1424-1429.
  • 43 Broudy VC, Lin NL, Sabath DF, Papayannopoulou T, Kaushansky K. Human platelets display high affinity receptors for thrombopoietin. Blood 1997; 89: 1896-1904.
  • 44 Baumgartner JW, Wells CA, Chen C-M, Waters MJ. The role of the WSXWS equivalent motif in growth hormone receptor function. J Biol Chem. 1994; 269: 29094-29101.
  • 45 Alexander WS, Metcalf D, Dunn AR. Point mutations within a dimer interface homology domain of c-Mpl induce constitutive receptor activity and tumorigenicity. EMBO J. 1995; 14: 5569-5578.
  • 46 Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, Vanin EF, Bodner S, Colamonici OR, van Deursen JM, Grosveld G, Ihle JN. JAK2 is essential for signaling through a variety of cytokine receptors. Cell. 1998; 93: 385-395.
  • 47 Drachman JG, Millet KM, Kaushansky K. Mpl signal transduction requires functional JaK2 not TYK2. J Biol Chem.. In press.
  • 48 Drachman J, Griffin JD, Kaushansky K. Stimulation of tyrosine kinase activity by MPL-ligand (thrombopoietin). J Biol Chem. 1995; 270: 4979-4982.
  • 49 Sasaki K, Odai H, Hanazono Y, Ueno H, Ogawa S, Langdon WY, Tanaka T, Miyagawa K, Mitani K, Yazaki Y. et al. TPO/c-mpl ligand induces tyrosine phosphorylation of multiple cellular proteins including proto-oncogene products, Vav and c-Cbl, and Ras signaling molecules. Biochem Biophys Res Commun. 1995; 216: 338-347.
  • 50 Miyakawa Y, Oda A, Druker BJ, Kato T, Miyazaki H, Handa M, Ikeda Y. Recombinant thrombopoietin induces rapid protein tyrosine phosphorylation of Janus kinase 2 and Shc in human blood platelets. Blood 1995; 86: 23-27.
  • 51 Sattler M, Durstin MA, Frank DA, Okuda K, Kaushansky K, Salgia R, Griffin JD. The thrombopoietin receptor c-Mpl activates JAK2 and TYK2 tyrosine kinases. Exp Hematol. 1995; 23: 1040-1048.
  • 52 Alexander WS, Maurer AB, Novak U, Harrison-Smith M. Tyrosine-599 of the c-Mpl receptor is required for Shc phosphorylation and the induction of cellular differentiation. EMBO J. 1996; 16: 6531-6540.
  • 53 Drachman JD, Sabath DF, Fox NE, Kaushansky K. Thrombopoietin (TPO) induces tyrosine phosphorylation of JAK2, TYK 2, STAT 3 and STAT 5b in MKs. Blood 1997; 89: 483-492.
  • 54 Joneja B, Wojchowski DM. Mitogenic signaling and inhibition of apoptosis via the erythropoietin receptor box-1 domain. J Biol Chem. 1997; 272: 11176-11184.
  • 55 Nakamura N, Chin H, Miyasaka N, Miura O. An epidermal growth factor receptor/JAK2 tyrosine kinase domain chimera induces tyrosine phosphorylation of Stat5 and transduces a growth signal in hematopoietic cells. J Biol Chem. 1996; 271: 19483-19488.
  • 56 de Sauvage FJ, Lipari T, Steinmetz H. et al. Activation of the MAPK pathway by c-mpl is not required for platelet production in vivo. Blood 1998; 92: 713a.
  • 57 Chida D, Miura O, Yoshimura A, Miyajima A. Role of cytokine signaling molecules in erythroid differentiation of mouse fetal liver hematopoietic cells: functional analysis of signaling molecules by retrovirus-mediated expression. Blood 1998; 92: 65a.
  • 58 Corey SJ, Dombrosky-Ferlan PM, Zuo S, Krohn E, Donnenberg AD, Zorich P, Romero G, Takata M, Kurosaki T. Requirement of Src kinase Lyn for induction of DNA synthesis by granulocyte colony stimulating factor. J Biol Chem. 1998; 273: 3230-3235.
  • 59 Qian X, Vass WC, Papageorge AG, Anborgh PH, Lowy DR. N terminus of Sos1 Ras exchange factor: critical roles for the Dbl and pleckstrin homology domains. Mol Cell Biol. 1998; 18: 771-778.
  • 60 Fabian JR, Daar IO, Morrison DK. Critical tyrosine residues regulate the enzymatic and biological activity of Raf-1 kinase. Mol Cell Biol. 1993; 13: 7170-7179.
  • 61 Cobb MH, Goldsmith EJ. How MAP kinases are regulated. J Biol Chem. 1995; 270: 14843-14846.
  • 62 Galaktionov K, Jessus C, Beach D. Raf1 interaction with Cdc25 phosphatase ties mitogenic signal transduction to cell cycle activation. Genes Dev. 1995; 9: 1046-1058.
  • 63 Wang HG, Rapp UR, Reed JC. Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell. 1996; 87: 629-638.
  • 64 Rouyez MC, Boucheron C, Gisselbrecht S, Dusanter-Fourt I, Porteu F. Control of thrombopoietin-induced megakaryocytic differentiation by the mitogen-activated protein kinase pathway. Mol Cell Biol. 1997; 17: 4991-5000.
  • 65 Kaushansky K, Lin N, Grossmann A, Humes J, Sprugel KH, Broudy VC. Thrombopoietin expands erythroid, granulocyte-macrophage and megakaryocytic progenitor cells in normal and myelosuppressed mice. Exp Hematol. 1996; 23: 265-269.
  • 66 Ulich TR, del Castillo J, Yin S, Swift S, Padilla D, Senaldi G, Bennett L, Shutter J, Bogenberger J, Sun D. et al. Megakaryocyte growth and development factor ameliorates carboplatin-induced thrombocytopenia in mice. Blood 1995; 86: 971-976.
  • 67 Akahori H, Shibuya K, Obuchi M, Nishizawa Y, Tsuji A, Kabaya K, Kusaka M, Ohashi H, Tsumura H, Kato T, Miyazaki H. Effect of recombinant human thrombopoietin in nonhuman primates with chemotherapy-induced thrombocytopenia. Br J Haematol. 1996; 94: 722-728.
  • 68 Harker LA, Marzec UM, Kelly AB, Cheung E, Tomer A, Nichol JL, Hanson SR, Stead RB. Prevention of thrombocytopenia and neutropenia in a nonhuman primate model of marrow suppressive chemotherapy by combining pegylated recombinant human megakaryocyte growth and development factor and recombinant human granulocyte colony-stimulating factor. Blood 1997; 89: 155-165.
  • 69 Grossmann A, Lenox J, Ren HP, Humes JM, Forstrom JW, Kaushansky K, Sprugel KH. Thrombopoietin accelerates platelet, red blood cell and neutrophil recovery in myelosuppressed mice. Exp Heme. 1996; 24: 1238-46.
  • 70 Neelis KJ, Qingliang L, Thomas GR, Cohen BL, Eaton DL, Wagemaker G. Prevention of thrombocytopenia by thrombopoietin in myelosuppressed rhesus monkeys accompanied by prominent erythropoietic stimulation and iron depletion. Blood 1997; 90: 58-63.
  • 71 Molineux G, Hartley CA, McElroy P, McCrea C, McNiece IK. Megakaryocyte growth and development factor stimulates enhanced platelet recovery in mice after bone marrow transplantation. Blood 1996; 88: 1509-1514.
  • 72 Kabaya K, Shibuya K, Torii Y, Nitta Y, Ida M, Akahori H, Kato T, Kusaka M, Miyazaki H. Improvement of thrombocytopenia following bone marrow transplantation by pegylated recombinant human megakaryocyte growth and development factor in mice. Bone Marrow Transplant. 1996; 18: 1035-1041.
  • 73 Fibbe WE, Heemskerk DPM, Laterveer L, Pruijt JF, Foster D, Kaushansky K, Willemze R. Accelerated reconstitution of platelets and erythrocytes following syngeneic transplantation of bone marrow cells derived from thrombopoietin pretreated donor mice. Blood 1995; 86: 3308-3313.
  • 74 Molineux G, Hartley C, McElroy P, McCrea C, McNiece IK. Megakaryocyte growth and development factor accelerates platelet recovery in peripheral blood progenitor cell transplant recipients. Blood 1996; 88: 366-376.
  • 75 Basser RL, Rasko JEJ, Clarke K, Cebon J, Green MD, Hussein S, Alt C, Menchaca D, Tomita D, Marty J, Fox RM, Begley CG. Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in patients with advanced cancer. Lancet. 1996; 348: 1279-1281.
  • 76 Fanucchi M, Glaspy J, Crawford J, Garst J, Figlin R, Sheridan W, Menchaca D, Tomita D, Ozer H, Harker L. Effects of polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor on platelet counts after chemotherapy for lung cancer. N Engl J Med. 1997; 336: 404-409.
  • 77 Vadhan-Raj S, Verschraegen C, McGarry L. et al. Recombinant human thrombopoietin (rhTPO) attenuates high-dose carboplatin (C)-induced thrombocytopenia in patients with gynecologic malignancy. Blood 1997; 90: 580a.
  • 78 Basser RL, Rasko JE, Clarke K, Cebon J, Green MD, Grigg AP, Zalcberg J, Cohen B, O’Byrne J, Menchaca DM, Fox RM, Begley CG. Randomized, blinded, placebo-controlled phase I trial of pegylated recombinant human megakaryocyte growth and development factor with filigrastim after dose-intensive chemotherapy in patients with advanced cancer. Blood 1997; 89: 3118-3128.
  • 79 Beveridge R, Schuster M, Waller E. et al. Randomized, double-blind, placebo-controlled trial of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in breast cancer patients following autologous bone marrow transplantation (ABMT). Blood 1997; 90: 580a.
  • 80 Glaspy J, Vredenburgh J, Demetri GD. et al. Effects of PEGylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) before high dose chemotherapy (HDC) with peripheral blood progenitor cell (PBPC) support. Blood 1997; 90: 580a.
  • 81 Bolwell B, Vredenburgh J, Overmoyer B. et al. Safety and biologic effect of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in breast cancer patients following autologous peripheral blood progenitor cell transplantation (PBPC). Blood 1997; 90: 171a.
  • 82 Somol G, Sniecinski I, Veer A, Longmate J, Knutson G, Vuk-Pavolovic S, Bhatia R, Chow W, Leong L, Morgan R, Margolin K, Raschko J, Shibata S, Tetef M, Yen Y, Forman S, Jones D, Ashby M, Fyfe G, Hellmann S, Doroshow JH. Recombinant human thrombopoietin in combination with granulocyte colony-stimulating factor enhances mobilization of peripheral blood progenitor cells, increases peripheral blood platelet concentration, and accelerates hematopoietic recovery following high-donse chemotherapy. Blood 1999; 93: 2798-2806.