Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin

doi:10.1084/jem.183.2.651

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Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin

FJ de Sauvage, K Carver-Moore, SM Luoh, A Ryan, M Dowd, DL Eaton and MW Moore
Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.

Thrombopoietin (TPO) has recently been cloned and shown to regulate megakaryocyte and platelet production by activating the cytokine receptor c-mpl. To determine whether TPO is the only ligand for c-mpl and the major regulator of megakaryocytopoiesis, TPO deficient mice were generated by gene targeting. TPO-/- mice have a >80% decrease in their platelets and megakaryocytes but have normal levels of all the other hematopoietic cell types. A gene dosage effect observed in heterozygous mice suggests that the TPO gene is constitutively expressed and that the circulating TPO level is directly regulated by the platelet mass. Bone marrow from TPO-/- mice have decreased numbers of megakaryocyte-committed progenitors as well as lower ploidy in the megakaryocytes that are present. These results demonstrate that TPO alone is the major physiological regulator of both proliferation and differentiation of hematopoietic progenitor cells into mature megakaryocytes but that TPO is not critical to the final step of platelet production.
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Kaushansky, K. (2008). Historical review: megakaryopoiesis and thrombopoiesis. Blood 111: 981-986 [Abstract] [Full Text]
Abkowitz, J. L., Chen, J. (2007). Studies of c-Mpl function distinguish the replication of hematopoietic stem cells from the expansion of differentiating clones. Blood 109: 5186-5190 [Abstract] [Full Text]
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Kaushansky, K. (2006). Lineage-specific hematopoietic growth factors.. NEJM 354: 2034-2045 [Full Text]
Amano, H., Hackett, N. R., Rafii, S., Crystal, R. G. (2005). Thrombopoietin Gene Transfer-Mediated Enhancement of Angiogenic Responses to Acute Ischemia. Circ. Res. 97: 337-345 [Abstract] [Full Text]
Kanaji, T., Russell, S., Cunningham, J., Izuhara, K., Fox, J. E. B., Ware, J. (2004). Megakaryocyte proliferation and ploidy regulated by the cytoplasmic tail of glycoprotein Ib{alpha}. Blood 104: 3161-3168 [Abstract] [Full Text]
Tong, W., Lodish, H. F. (2004). Lnk Inhibits Tpo-mpl Signaling and Tpo-mediated Megakaryocytopoiesis. JEM 200: 569-580 [Abstract] [Full Text]
Antonchuk, J., Hyland, C. D., Hilton, D. J., Alexander, W. S. (2004). Synergistic effects on erythropoiesis, thrombopoiesis, and stem cell competitiveness in mice deficient in thrombopoietin and steel factor receptors. Blood 104: 1306-1313 [Abstract] [Full Text]
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Kamata, T., Pritchard, C. A., Leavitt, A. D. (2004). Raf-1 is not required for megakaryocytopoiesis or TPO-induced ERK phosphorylation. Blood 103: 2568-2570 [Abstract] [Full Text]
Kuter, D. J., Begley, C. G. (2002). Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood 100: 3457-3469 [Abstract] [Full Text]
Haznedaroglu, I. C., Goker, H., Turgut, M., Buyukasik, Y., Benekli, M. (2002). Thrombopoietin as a Drug: Biologic Expectations, Clinical Realities, and Future Directions. CLIN APPL THROMB HEMOST 8: 193-212 [Abstract]
Kaushansky, K., Fox, N., Lin, N. L., Liles, W. C. (2002). Lineage-specific growth factors can compensate for stem and progenitor cell deficiencies at the postprogenitor cell level: an analysis of doubly TPO- and G-CSF receptor-deficient mice. Blood 99: 3573-3578 [Abstract] [Full Text]
Kirito, K., Osawa, M., Morita, H., Shimizu, R., Yamamoto, M., Oda, A., Fujita, H., Tanaka, M., Nakajima, K., Miura, Y., Ozawa, K., Komatsu, N. (2002). A functional role of Stat3 in in vivo megakaryopoiesis. Blood 99: 3220-3227 [Abstract] [Full Text]
Kirito, K., Watanabe, T., Sawada, K.-i., Endo, H., Ozawa, K., Komatsu, N. (2002). Thrombopoietin Regulates Bcl-xL Gene Expression through Stat5 and Phosphatidylinositol 3-Kinase Activation Pathways. J. Biol. Chem. 277: 8329-8337 [Abstract] [Full Text]
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Li, J., Yang, C., Xia, Y., Bertino, A., Glaspy, J., Roberts, M., Kuter, D. J. (2001). Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 98: 3241-3248 [Abstract] [Full Text]
Kaser, A., Brandacher, G., Steurer, W., Kaser, S., Offner, F. A., Zoller, H., Theurl, I., Widder, W., Molnar, C., Ludwiczek, O., Atkins, M. B., Mier, J. W., Tilg, H. (2001). Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood 98: 2720-2725 [Abstract] [Full Text]
Levin, J., Cocault, L., Demerens, C., Challier, C., Pauchard, M., Caen, J., Souyri, M. (2001). Thrombocytopenic c-mpl{-}/{-} mice can produce a normal level of platelets after administration of 5-fluorouracil: the effect of age on the response. Blood 98: 1019-1027 [Abstract] [Full Text]
Gaur, M., Murphy, G. J., deSauvage, F. J., Leavitt, A. D. (2001). Characterization of Mpl mutants using primary megakaryocyte-lineage cells from mpl{-}/{-} mice: a new system for Mpl structure-function studies. Blood 97: 1653-1661 [Abstract] [Full Text]
Drachman, J. G., Jarvik, G. P., Mehaffey, M. G. (2000). Autosomal dominant thrombocytopenia: incomplete megakaryocyte differentiation and linkage to human chromosome 10. Blood 96: 118-125 [Abstract] [Full Text]
Matsumura, I., Tanaka, H., Kawasaki, A., Odajima, J., Daino, H., Hashimoto, K., Wakao, H., Nakajima, K., Kato, T., Miyazaki, H., Kanakura, Y. (2000). Increased D-type Cyclin Expression Together with Decreased cdc2 Activity Confers Megakaryocytic Differentiation of a Human Thrombopoietin-dependent Hematopoietic Cell Line. J. Biol. Chem. 275: 5553-5559 [Abstract] [Full Text]
Luoh, S.-M., Stefanich, E., Solar, G., Steinmetz, H., Lipari, T., Pestina, T. I., Jackson, C. W., de Sauvage, F. J. (2000). Role of the Distal Half of the c-Mpl Intracellular Domain in Control of Platelet Production by Thrombopoietin In Vivo. Mol. Cell. Biol. 20: 507-515 [Abstract] [Full Text]
Gainsford, T., Nandurkar, H., Metcalf, D., Robb, L., Begley, C. G., Alexander, W. S. (2000). The residual megakaryocyte and platelet production in c-Mpl-deficient mice is not dependent on the actions of interleukin-6, interleukin-11, or leukemia inhibitory factor. Blood 95: 528-534 [Abstract] [Full Text]
Rojnuckarin, P., Drachman, J. G., Kaushansky, K. (1999). Thrombopoietin-Induced Activation of the Mitogen-Activated Protein Kinase (MAPK) Pathway in Normal Megakaryocytes: Role in Endomitosis. Blood 94: 1273-1282 [Abstract] [Full Text]
Madoiwa, S., Komatsu, N., Mimuro, J., Kimura, K., Matsuda, M., Sakata, Y. (1999). Developmental Expression of Plasminogen Activator Inhibitor-1 Associated With Thrombopoietin-Dependent Megakaryocytic Differentiation. Blood 94: 475-482 [Abstract] [Full Text]
Ryan, A. M. (1999). Commentary: Role of the Pathologist in the Identification and Characterization of Therapeutic Molecules. Toxicol Pathol 27: 474-476
Cohen-Solal, K., Vitrat, N., Titeux, M., Vainchenker, W., Wendling, F. (1999). High-Level Expression of Mpl in Platelets and Megakaryocytes Is Independent of Thrombopoietin. Blood 93: 2859-2866 [Abstract] [Full Text]
Chang, M., Qian, J. X., Lee, S. m., Joubran, J., Fernandez, G., Nichols, J., Knoppel, A., Buzby, J. S. (1999). Tissue Uptake of Circulating Thrombopoietin Is Increased in Immune-Mediated Compared With Irradiated Thrombocytopenic Mice. Blood 93: 2515-2524 [Abstract] [Full Text]
Taksin, A. L., Couedic, J.-P. L., Dusanter-Fourt, I., Masse, A., Giraudier, S., Katz, A., Wendling, F., Vainchenker, W., Casadevall, N., Debili, N. (1999). Autonomous Megakaryocyte Growth in Essential Thrombocythemia and Idiopathic Myelofibrosis Is Not Related to a c-mpl Mutation or to an Autocrine Stimulation by Mpl-L. Blood 93: 125-139 [Abstract] [Full Text]
Ghilardi, N., Wiestner, A., Skoda, R. C. (1998). Thrombopoietin Production Is Inhibited by a Translational Mechanism. Blood 92: 4023-4030 [Abstract] [Full Text]
Deng, B., Banu, N., Malloy, B., Hass, P., Wang, J. F., Cavacini, L., Eaton, D., Avraham, H. (1998). An Agonist Murine Monoclonal Antibody to the Human c-Mpl Receptor Stimulates Megakaryocytopoiesis. Blood 92: 1981-1988 [Abstract] [Full Text]
Qian, S., Fu, F., Li, W., Chen, Q., de Sauvage, F. J. (1998). Primary Role of the Liver in Thrombopoietin Production Shown by Tissue-Specific Knockout. Blood 92: 2189-2191 [Full Text]
Kaushansky, K. (1998). Thrombopoietin. NEJM 339: 746-754 [Full Text]
Neelis, K. J., Visser, T. P., Dimjati, W., Thomas, G. R., Fielder, P. J., Bloedow, D., Eaton, D. L., Wagemaker, G. (1998). A Single Dose of Thrombopoietin Shortly After Myelosuppressive Total Body Irradiation Prevents Pancytopenia in Mice by Promoting Short-Term Multilineage Spleen-Repopulating Cells at the Transient Expense of Bone Marrow-Repopulating Cells. Blood 92: 1586-1597 [Abstract] [Full Text]
Kondo, T., Okabe, M., Sanada, M., Kurosawa, M., Suzuki, S., Kobayashi, M., Hosokawa, M., Asaka, M. (1998). Familial Essential Thrombocythemia Associated With One-Base Deletion in the 5'-Untranslated Region of the Thrombopoietin Gene. Blood 92: 1091-1096 [Abstract] [Full Text]
Hamada, T., Mohle, R., Hesselgesser, J., Hoxie, J., Nachman, R. L., Moore, M. A.S., Rafii, S. (1998). Transendothelial Migration of Megakaryocytes in Response to Stromal Cell-derived Factor 1 (SDF-1) Enhances Platelet Formation. JEM 188: 539-548 [Abstract] [Full Text]
Matsumura, I., Nakajima, K., Wakao, H., Hattori, S., Hashimoto, K., Sugahara, H., Kato, T., Miyazaki, H., Hirano, T., Kanakura, Y. (1998). Involvement of Prolonged Ras Activation in Thrombopoietin-Induced Megakaryocytic Differentiation of a Human Factor-Dependent Hematopoietic Cell Line. Mol. Cell. Biol. 18: 4282-4290 [Abstract] [Full Text]
Solar, G. P., Kerr, W. G., Zeigler, F. C., Hess, D., Donahue, C., de Sauvage, F. J., Eaton, D. L. (1998). Role of c-mpl in Early Hematopoiesis. Blood 92: 4-10 [Abstract] [Full Text]
Williams, J. L., Pipia, G. G., Datta, N. S., Long, M. W. (1998). Thrombopoietin Requires Additional Megakaryocyte-Active Cytokines for Optimal Ex Vivo Expansion of Megakaryocyte Precursor Cells. Blood 91: 4118-4126 [Abstract] [Full Text]
Abina, M.-A., Tulliez, M., Duffour, M.-T., Debili, N., Lacout, C., Villeval, J.-L., Wendling, F., Vainchenker, W., Haddada, H. (1998). Thrombopoietin (TPO) Knockout Phenotype Induced by Cross-Reactive Antibodies Against TPO Following Injection of Mice with Recombinant Adenovirus Encoding Human TPO. J. Immunol. 160: 4481-4489 [Abstract] [Full Text]
Gainsford, T., Roberts, A. W., Kimura, S., Metcalf, D., Dranoff, G., Mulligan, R. C., Begley, C. G., Robb, L., Alexander, W. S. (1998). Cytokine Production and Function in c-mpl-Deficient Mice: No Physiologic Role for Interleukin-3 in Residual Megakaryocyte and Platelet Production. Blood 91: 2745-2752 [Abstract] [Full Text]
Kimura, S., Roberts, A. W., Metcalf, D., Alexander, W. S. (1998). Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for�thrombopoietin. Proc. Natl. Acad. Sci. USA 95: 1195-1200 [Abstract] [Full Text]
Hong, Y., Dumenil, D., van der Loo, B., Goncalves, F., Vainchenker, W., Erusalimsky, J. D. (1998). Protein Kinase C Mediates the Mitogenic Action of Thrombopoietin in c-Mpl-Expressing UT-7 Cells. Blood 91: 813-822 [Abstract] [Full Text]
Norol, F., Vitrat, N., Cramer, E., Guichard, J., Burstein, S. A., Vainchenker, W., Debili, N. (1998). Effects of Cytokines on Platelet Production From Blood and Marrow CD34+ Cells. Blood 91: 830-843 [Abstract] [Full Text]
Daw, N. C., Arnold, J. T., Abushullaih, B. A., Stenberg, P. E., White, M. M., Jayawardene, D., Kumar Srivastava, D., Jackson, C. W. (1998). A Single Intravenous Dose of Murine Megakaryocyte Growth and Development Factor Potently Stimulates Platelet Production, Challenging the Necessity for Daily Administration. Blood 91: 466-474 [Abstract] [Full Text]
Ishida, Y., Ito, T., Kuriya, S.-i. (1998). Effects of C-Mpl Ligand on Cytoplasmic Maturation of Murine Megakaryocytes and on Platelet Production. J. Histochem. Cytochem. 46: 49-58 [Abstract] [Full Text]
Heil, G., Hoelzer, D., Sanz, M. A., Lechner, K., Liu Yin, J. A., Papa, G., Noens, L., Szer, J., Ganser, A., O'Brien, C., Matcham, J., Barge, A. (1997). A Randomized, Double-Blind, Placebo-Controlled, Phase III Study of Filgrastim in Remission Induction and Consolidation Therapy for Adults With De Novo Acute Myeloid Leukemia. Blood 90: 4710-4718 [Abstract] [Full Text]
Horikawa, Y., Matsumura, I., Hashimoto, K., Shiraga, M., Kosugi, S., Tadokoro, S., Kato, T., Miyazaki, H., Tomiyama, Y., Kurata, Y., Matsuzawa, Y., Kanakura, Y. (1997). Markedly Reduced Expression of Platelet c-mpl Receptor in Essential Thrombocythemia. Blood 90: 4031-4038 [Abstract] [Full Text]
Bunting, S., Widmer, R., Lipari, T., Rangell, L., Steinmetz, H., Carver-Moore, K., Moore, M. W., Keller, G.-A., de Sauvage, F. J. (1997). Normal Platelets and Megakaryocytes Are Produced In Vivo in the Absence of Thrombopoietin. Blood 90: 3423-3429 [Abstract] [Full Text]
Dale, D. C., Nichol, J. L., Rich, D. A., Best, D. M., Slichter, S. J., Sheridan, W., Hunt, P. (1997). Chronic Thrombocytopenia Is Induced in Dogs by Development of Cross-Reacting Antibodies to the MpL Ligand. Blood 90: 3456-3461 [Abstract] [Full Text]
Abraham, R., Basser, R. L. (1997). Megakaryocyte Growth and Development Factor: A Review of Early Clinical Studies. The Oncologist 2: 311-318 [Abstract] [Full Text]
Neelis, K. J., Hartong, S. C.C., Egeland, T., Thomas, G. R., Eaton, D. L., Wagemaker, G. (1997). The Efficacy of Single-Dose Administration of Thrombopoietin With Coadministration of Either Granulocyte/Macrophage or Granulocyte Colony-Stimulating Factor in Myelosuppressed Rhesus Monkeys. Blood 90: 2565-2573 [Abstract] [Full Text]
Shivdasani, R. A., Fielder, P., Keller, G.-A., Orkin, S. H., de Sauvage, F. J. (1997). Regulation of the Serum Concentration of Thrombopoietin in Thrombocytopenic NF-E2 Knockout Mice. Blood 90: 1821-1827 [Abstract] [Full Text]
Stefanich, E., Senn, T., Widmer, R., Fratino, C., Keller, G.-A., Fielder, P. J. (1997). Metabolism of Thrombopoietin (TPO) In Vivo: Determination of the Binding Dynamics for TPO in Mice. Blood 89: 4063-4070 [Abstract] [Full Text]
Goncalves, F., Lacout, C., Villeval, J.-L., Wendling, F., Vainchenker, W., Dumenil, D. (1997). Thrombopoietin Does Not Induce Lineage-Restricted Commitment of Mpl-R Expressing Pluripotent Progenitors But Permits Their Complete Erythroid and Megakaryocytic Differentiation. Blood 89: 3544-3553 [Abstract] [Full Text]
Broudy, V. C., Lin, N. L., Sabath, D. F., Papayannopoulou, T., Kaushansky, K. (1997). Human Platelets Display High-Affinity Receptors for Thrombopoietin. Blood 89: 1896-1904 [Abstract] [Full Text]
Fanucchi, M., Glaspy, J., Crawford, J., Garst, J., Figlin, R., Sheridan, W., Menchaca, D., Tomita, D., Ozer, H., Harker, L. (1997). Effects of Polyethylene Glycol-Conjugated Recombinant Human Megakaryocyte Growth and Development Factor on Platelet Counts after Chemotherapy for Lung Cancer. NEJM 336: 404-409 [Abstract] [Full Text]
Arnold, J. T., Daw, N. C., Stenberg, P. E., Jayawardene, D., Srivastava, D. K., Jackson, C. W. (1997). A Single Injection of Pegylated Murine Megakaryocyte Growth and Development Factor (MGDF ) Into Mice Is Sufficient to Produce a Profound Stimulation of Megakaryocyte Frequency, Size, and Ploidization. Blood 89: 823-833 [Abstract] [Full Text]
Kimura, Y., Hart, A., Hirashima, M., Wang, C., Holmyard, D., Pittman, J., Pang, X.-L., Jackson, C. W., Bernstein, A. (2002). Zinc Finger Protein, Hzf, Is Required for Megakaryocyte Development and Hemostasis. JEM 195: 941-952 [Abstract] [Full Text]