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Gene Review

Thpo  -  thrombopoietin

Mus musculus

Synonyms: C-mpl ligand, MGDF, ML, Megakaryocyte colony-stimulating factor, Megakaryocyte growth and development factor, ...
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Disease relevance of Thpo

  • However, these mice remain healthy and show no signs of spontaneous hemorrhage, implying that TPO-independent mechanisms for platelet production exist and are sufficient for hemostasis [1].
  • The erythropoietin-like domain of TPO (TPO1-153) has been fused to the gIII coat protein of M13 bacteriophage [2].
  • Thrombopoietin is essential for the maintenance of normal hematopoiesis in humans: development of aplastic anemia in patients with congenital amegakaryocytic thrombocytopenia [3].
  • Upon hypoxia, EPO and its receptor are rapidly reexpressed, whereas neuronal TPO and its receptor are down-regulated [4].
  • Mice harboring genetic alterations in either the extrinsic (ectopic thrombopoietin expression, TPO(high) mice) or intrinsic (hypomorphic GATA-1 mutation, GATA-1(low) mice) control of Mk differentiation develop myelofibrosis, a syndrome similar to IM [5].

Psychiatry related information on Thpo


High impact information on Thpo


Chemical compound and disease context of Thpo


Biological context of Thpo


Anatomical context of Thpo


Associations of Thpo with chemical compounds

  • This increase was especially apparent in TPO-deficient mice where numbers were increased to a level greater than in diluent-treated control mice and approached or equaled that in the TPO-treated control mice [20].
  • The ability of Tpo and SCF to synergistically enhance the growth of Lin- Sca-1+ progenitors was predominantly observed in the more primitive rhodamine 123(lo) fraction [22].
  • In addition, we constructed various mutant Mpl-type SAGs to abolish the responsiveness to endogenous TPO while retaining Tm-dependency [23].
  • In canine and murine models, serum levels of MGDF activity peak during the thrombocytopenic periods after irradiation, 5-fluorouracil, or antiplatelet antisera injections [24].
  • Enforced expression of c-mpl in embryonic stem (ES) cells inactivated for this gene results in protein expression in all the ES cell progeny, producing cells that do not belong to the megakaryocytic lineage and are responsive to PEG-rhuMGDF, a truncated form of human thrombopoietin (TPO) conjugated to polyethylene glycol [25].

Physical interactions of Thpo

  • Thrombopoietin (TPO) plays a critical role in megakaryopoiesis through binding to its receptor Mpl [26].
  • Numerous studies have shown that TPO binding leads to JAK2 kinase activation and Tyr phosphorylation of c-Mpl and several intracellular signaling intermediates, events vital for the biological activity of the hormone [27].

Enzymatic interactions of Thpo

  • Furthermore, the MEK-phosphorylating activity of protein kinase Czeta (PKCzeta) was also enhanced after TPO stimulation of T69Mpl, contributing to ERK activity [28].
  • This suggests that crk1 can be phosphorylated by a kinase other than p210bcr-abl and that crk1 may have a role in signaling by thrombopoietin [12].

Regulatory relationships of Thpo

  • Thus, the present studies show the potent ability of Tpo to enhance the growth of primitive multipotent murine BM progenitors in combination with multiple early acting cytokines and documents its unique ability to synergize with SCF to enhance Mk production from such progenitors [22].
  • Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors [29].
  • The c-mpl ligand mRNA was equally expressed both in parental M1 cells and in those transfected with the GATA-1 expression vector [30].
  • MATERIALS AND METHODS: A cassette coding for MplK cDNA was introduced into parental and MplP-expressing BaF3 cells and TPO-mediated cell growth studied [31].
  • These results support the concept that TPO behaves like an acute-phase protein in that its synthesis is induced by IL-6 in the liver [32].

Other interactions of Thpo

  • Thrombopoietin (TPO), the ligand for the receptor protooncogene c-mpl, has been cloned and shown to be the critical regulator of platelet production [18].
  • MGDF differentiation, as measured by decreased proliferation, changes in cellular morphology, increased adherence, and downregulation of very late antigen (VLA)-4, is dominant over IL-3 proliferation [33].
  • Thrombopoietin production in wild-type and interleukin-6 knockout mice with acute inflammation [32].
  • Upon mobilization of HPC from BM into blood after CY, the expression of SCF, TPO, SDF-1 and TGFbeta1 tends to decrease in BM [34].
  • Thus, Lnk negatively modulates mpl signaling pathways and is important for Tpo-mediated megakaryocytopoiesis in vivo [16].

Analytical, diagnostic and therapeutic context of Thpo


  1. 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. Gainsford, T., Nandurkar, H., Metcalf, D., Robb, L., Begley, C.G., Alexander, W.S. Blood (2000) [Pubmed]
  2. Mutational analysis of thrombopoietin for identification of receptor and neutralizing antibody sites. Pearce, K.H., Potts, B.J., Presta, L.G., Bald, L.N., Fendly, B.M., Wells, J.A. J. Biol. Chem. (1997) [Pubmed]
  3. Thrombopoietin is essential for the maintenance of normal hematopoiesis in humans: development of aplastic anemia in patients with congenital amegakaryocytic thrombocytopenia. Ballmaier, M., Germeshausen, M., Krukemeier, S., Welte, K. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
  4. A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain. Ehrenreich, H., Hasselblatt, M., Knerlich, F., von Ahsen, N., Jacob, S., Sperling, S., Woldt, H., Vehmeyer, K., Nave, K.A., Sirén, A.L. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  5. A pathobiologic pathway linking thrombopoietin, GATA-1, and TGF-beta1 in the development of myelofibrosis. Vannucchi, A.M., Bianchi, L., Paoletti, F., Pancrazzi, A., Torre, E., Nishikawa, M., Zingariello, M., Di Baldassarre, A., Rana, R.A., Lorenzini, R., Alfani, E., Migliaccio, G., Migliaccio, A.R. Blood (2005) [Pubmed]
  6. Developmental biology of thrombopoietin in the human fetus and neonate. Dame, C. Acta paediatrica (Oslo, Norway : 1992). Supplement. (2002) [Pubmed]
  7. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Shivdasani, R.A., Rosenblatt, M.F., Zucker-Franklin, D., Jackson, C.W., Hunt, P., Saris, C.J., Orkin, S.H. Cell (1995) [Pubmed]
  8. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Avecilla, S.T., Hattori, K., Heissig, B., Tejada, R., Liao, F., Shido, K., Jin, D.K., Dias, S., Zhang, F., Hartman, T.E., Hackett, N.R., Crystal, R.G., Witte, L., Hicklin, D.J., Bohlen, P., Eaton, D., Lyden, D., de Sauvage, F., Rafii, S. Nat. Med. (2004) [Pubmed]
  9. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Lok, S., Kaushansky, K., Holly, R.D., Kuijper, J.L., Lofton-Day, C.E., Oort, P.J., Grant, F.J., Heipel, M.D., Burkhead, S.K., Kramer, J.M. Nature (1994) [Pubmed]
  10. Cytokines regulate postnatal hematopoietic stem cell expansion: opposing roles of thrombopoietin and LNK. Buza-Vidas, N., Antonchuk, J., Qian, H., Månsson, R., Luc, S., Zandi, S., Anderson, K., Takaki, S., Nygren, J.M., Jensen, C.T., Jacobsen, S.E. Genes Dev. (2006) [Pubmed]
  11. Thrombocytopenic c-mpl(-/-) mice can produce a normal level of platelets after administration of 5-fluorouracil: the effect of age on the response. Levin, J., Cocault, L., Demerens, C., Challier, C., Pauchard, M., Caen, J., Souyri, M. Blood (2001) [Pubmed]
  12. Crkl is constitutively tyrosine phosphorylated in platelets from chronic myelogenous leukemia patients and inducibly phosphorylated in normal platelets stimulated by thrombopoietin. Oda, A., Miyakawa, Y., Druker, B.J., Ishida, A., Ozaki, K., Ohashi, H., Wakui, M., Handa, M., Watanabe, K., Okamoto, S., Ikeda, Y. Blood (1996) [Pubmed]
  13. Megakaryocyte growth and development factor ameliorates carboplatin-induced thrombocytopenia in mice. Ulich, T.R., del Castillo, J., Yin, S., Swift, S., Padilla, D., Senaldi, G., Bennett, L., Shutter, J., Bogenberger, J., Sun, D. Blood (1995) [Pubmed]
  14. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Lonial, S., Waller, E.K., Richardson, P.G., Jagannath, S., Orlowski, R.Z., Giver, C.R., Jaye, D.L., Francis, D., Giusti, S., Torre, C., Barlogie, B., Berenson, J.R., Singhal, S., Schenkein, D.P., Esseltine, D.L., Anderson, J., Xiao, H., Heffner, L.T., Anderson, K.C. Blood (2005) [Pubmed]
  15. Ticlopidine inhibits the prothrombotic effects of thrombopoietin and ameliorates survival after supralethal total body irradiation. Mouthon, M.A., Gaugler, M.H., Vandamme, M., Gourmelon, P., Wagemaker, G., Van der Meeren, A. Thromb. Haemost. (2002) [Pubmed]
  16. Lnk inhibits Tpo-mpl signaling and Tpo-mediated megakaryocytopoiesis. Tong, W., Lodish, H.F. J. Exp. Med. (2004) [Pubmed]
  17. Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. de Sauvage, F.J., Carver-Moore, K., Luoh, S.M., Ryan, A., Dowd, M., Eaton, D.L., Moore, M.W. J. Exp. Med. (1996) [Pubmed]
  18. Thrombopoietin expands erythroid progenitors, increases red cell production, and enhances erythroid recovery after myelosuppressive therapy. Kaushansky, K., Broudy, V.C., Grossmann, A., Humes, J., Lin, N., Ren, H.P., Bailey, M.C., Papayannopoulou, T., Forstrom, J.W., Sprugel, K.H. J. Clin. Invest. (1995) [Pubmed]
  19. Thrombopoietin promotes mixed lineage and megakaryocytic colony-forming cell growth but inhibits primitive and definitive erythropoiesis in cells isolated from early murine yolk sacs. Xie, X., Chan, R.J., Johnson, S.A., Starr, M., McCarthy, J., Kapur, R., Yoder, M.C. Blood (2003) [Pubmed]
  20. Low levels of erythroid and myeloid progenitors in thrombopoietin-and c-mpl-deficient mice. Carver-Moore, K., Broxmeyer, H.E., Luoh, S.M., Cooper, S., Peng, J., Burstein, S.A., Moore, M.W., de Sauvage, F.J. Blood (1996) [Pubmed]
  21. Thrombopoietin, but not erythropoietin promotes viability and inhibits apoptosis of multipotent murine hematopoietic progenitor cells in vitro. Borge, O.J., Ramsfjell, V., Veiby, O.P., Murphy, M.J., Lok, S., Jacobsen, S.E. Blood (1996) [Pubmed]
  22. Thrombopoietin, but not erythropoietin, directly stimulates multilineage growth of primitive murine bone marrow progenitor cells in synergy with early acting cytokines: distinct interactions with the ligands for c-kit and FLT3. Ramsfjell, V., Borge, O.J., Veiby, O.P., Cardier, J., Murphy, M.J., Lyman, S.D., Lok, S., Jacobsen, S.E. Blood (1996) [Pubmed]
  23. New selective amplifier genes containing c-Mpl for hematopoietic cell expansion. Nagashima, T., Ueda, Y., Hanazono, Y., Kume, A., Shibata, H., Ageyama, N., Terao, K., Ozawa, K., Hasegawa, M. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  24. Purification and biologic characterization of plasma-derived megakaryocyte growth and development factor. Hunt, P., Li, Y.S., Nichol, J.L., Hokom, M.M., Bogenberger, J.M., Swift, S.E., Skrine, J.D., Hornkohl, A.C., Lu, H., Clogston, C. Blood (1995) [Pubmed]
  25. Requirement for mitogen-activated protein kinase activation in the response of embryonic stem cell-derived hematopoietic cells to thrombopoietin in vitro. Filippi, M.D., Porteu, F., Pesteur, F.L., Schiavon, V., Millot, G.A., Vainchenker, W., de Sauvage, F.J., Dubart Kupperschmitt, A., Sainteny, F. Blood (2002) [Pubmed]
  26. Distinct effects of thrombopoietin depending on a threshold level of activated Mpl in BaF-3 cells. Millot, G.A., Vainchenker, W., Duménil, D., Svinarchuk, F. J. Cell. Sci. (2002) [Pubmed]
  27. A structure-function analysis of serine/threonine phosphorylation of the thrombopoietin receptor, c-Mpl. Miyakawa, Y., Drachman, J.G., Gallis, B., Kaushansky, A., Kaushansky, K. J. Biol. Chem. (2000) [Pubmed]
  28. The roles of phosphatidylinositol 3-kinase and protein kinase Czeta for thrombopoietin-induced mitogen-activated protein kinase activation in primary murine megakaryocytes. Rojnuckarin, P., Miyakawa, Y., Fox, N.E., Deou, J., Daum, G., Kaushansky, K. J. Biol. Chem. (2001) [Pubmed]
  29. Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors. Lannutti, B.J., Drachman, J.G. Blood (2004) [Pubmed]
  30. Forced GATA-1 expression in the murine myeloid cell line M1: induction of c-Mpl expression and megakaryocytic/erythroid differentiation. Yamaguchi, Y., Zon, L.I., Ackerman, S.J., Yamamoto, M., Suda, T. Blood (1998) [Pubmed]
  31. MplK, a natural variant of the thrombopoietin receptor with a truncated cytoplasmic domain, binds thrombopoietin but does not interfere with thrombopoietin-mediated cell growth. Millot, G.A., Feger, F., Garçon, L., Vainchenker, W., Dumenil, D., Svinarchuk, F. Exp. Hematol. (2002) [Pubmed]
  32. Thrombopoietin production in wild-type and interleukin-6 knockout mice with acute inflammation. Burmester, H., Wolber, E.M., Freitag, P., Fandrey, J., Jelkmann, W. J. Interferon Cytokine Res. (2005) [Pubmed]
  33. Megakaryocyte growth and development factor and interleukin-3 induce patterns of protein-tyrosine phosphorylation that correlate with dominant differentiation over proliferation of mpl-transfected 32D cells. Mu, S.X., Xia, M., Elliott, G., Bogenberger, J., Swift, S., Bennett, L., Lappinga, D.L., Hecht, R., Lee, R., Saris, C.J. Blood (1995) [Pubmed]
  34. Cytokine gene expression in regenerating haematopoietic tissues of mice after cyclophosphamide treatment. Psenák, O., Sefc, L., Sýkora, V., Chang, K.T., Necas, E. Acta Haematol. (2003) [Pubmed]
  35. In vitro megakaryocytopoietic and thrombopoietic activity of c-mpl ligand (TPO) on purified murine hematopoietic stem cells. Zeigler, F.C., de Sauvage, F., Widmer, H.R., Keller, G.A., Donahue, C., Schreiber, R.D., Malloy, B., Hass, P., Eaton, D., Matthews, W. Blood (1994) [Pubmed]
  36. Thrombopoietin induces association of Crkl with STAT5 but not STAT3 in human platelets. Ozaki, K., Oda, A., Wakao, H., Rhodes, J., Druker, B.J., Ishida, A., Wakui, M., Okamoto, S., Morita, K., Handa, M., Komatsu, N., Ohashi, H., Miyajima, A., Ikeda, Y. Blood (1998) [Pubmed]
  37. High-level expression of Mpl in platelets and megakaryocytes is independent of thrombopoietin. Cohen-Solal, K., Vitrat, N., Titeux, M., Vainchenker, W., Wendling, F. Blood (1999) [Pubmed]
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