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THPO  -  thrombopoietin

Homo sapiens

 
 
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Disease relevance of THPO

  • However, the biologic effects of TPO on human acute myeloblastic leukemia (AML) cells are largely unknown [1].
  • Here, we show that TPO, interleukin-3 (IL-3) and, at least in short-term assays, also interferon gamma (IFN gamma) induced proliferation in acute myeloid leukemia (AML-M7)-derived M-07e cells [2].
  • Identification of TPO, the c-Mpl ligand, as the primary physiologic regulator of megakaryocyte and platelet development offers important promise for treatment of thrombocytopenia [3].
  • To study whether IFN interferes with hepatic thrombopoietin (TPO) synthesis, we used the human hepatoma cell line HepG2 [4].
  • To understand the mechanism of the transient thrombocytosis in preterm infants we firstly evaluated a correlation between platelet counts and thrombopoietin (TPO) levels in preterm infants and next c-mpl mRNA levels on platelets in healthy preterm infants longitudinally during a half-year of life [5].
 

High impact information on THPO

  • We derived an intragenic CA marker for the human THPO gene and performed linkage analysis in fourteen informative meioses in this family [6].
  • RESULTS: In the 38 patients who received MGDF after chemotherapy, the median nadir platelet count was 188,000 per cubic millimeter (range, 68,000 to 373,000), as compared with 111,000 per cubic millimeter (range, 21,000 to 307,000) in 12 patients receiving placebo (P = 0.013) [7].
  • CONCLUSIONS: MGDF has potent stimulatory effects on platelet production in patients with chemotherapy-induced thrombocytopenia [7].
  • METHODS: We conducted a randomized, double-blind, placebo-controlled dose-escalation study of MGDF in 53 patients with lung cancer who were treated with carboplatin and paclitaxel [7].
  • The patients were randomly assigned in blocks of 4 in a 1:3 ratio to receive either placebo or MGDF (0.03, 0.1, 0.3, 1.0, 3.0, or 5.0 microg per kilogram of body weight per day), injected subcutaneously [7].
 

Chemical compound and disease context of THPO

 

Biological context of THPO

 

Anatomical context of THPO

  • Human megakaryocyte progenitor development was potentiated by hTPO alone and further augmented in the presence of the early-acting cytokines (IL-3) or kit ligand/stem cell factor (KL/SCF) [15].
  • To further confirm the relationship between CpG demethylation and expression of GPVI in primary cells, we treated human cord blood cells with TPO [16].
  • Moreover, we show that the combination of IL-16 plus TPO induces the generation of tolerogenic DCs, able to induce an anergic state in T cells that persists when T cells are rechallenged with immunogenic DCs [17].
  • In this study we investigate the regulation of GPVI expression and show that thrombopoietin induces its expression in the megakaryocytic cell line UT-7/TPO [18].
  • Interestingly, TPO markedly augmented the EE for committed progenitors, including CFU-GM, erythroid burst-forming units (BFU-E), and CFU-Mix, in the presence of SCF + IL-3 or FL + IL-3 [19].
 

Associations of THPO with chemical compounds

  • A fraction of the TPO-dependent platelet attachment to a collagen-coated surface was insensitive to treatment with prostaglandin E1 [13].
  • AG490, a specific inhibitor for Jak2, and LY294002, a specific inhibitor for phosphatidylinositol (PI) 3-kinase, reduced the protein level of Bcl-xL in UT-7/TPO cells, accompanied by an increase in the ratio of apoptotic cells [20].
  • MATERIALS AND METHODS: Mks were generated from mobilized peripheral blood (PB) CD34+ cells from normal donors in serum-free medium with TPO, IL-3, and Flt3-ligand at 20% and 5% O2 [21].
  • Glucose uptake was significantly raised by elevation of cytosolic Ca(2+) concentration ([Ca(2+)](c)) with thapsigargin, this effect being additive to the activation induced by cytokines (SCF, GM-CSF and TPO) and hydrogen peroxide [22].
  • To clarify them further, we used a human megakaryoblastic cell line, Meg-J, which showed prominant polyploidization and augmented platelet glycoprotein (GP) Ib expression after incubation with thrombopoietin (TPO, c-mpl ligand) and K252a (an indolocarbasole derivative) [23].
 

Physical interactions of THPO

  • A reporter assay with various lengths of Bcl-x gene promoter revealed that both Stat- and nuclear factor kappa B-binding sites are prerequisites for TPO-induced promoter activity [20].
  • We found that TPO did not activate phospholipase C in human platelets and was unable to restore ADP-induced phospholipase C activation upon blockade of the G(q)-coupled P2Y1 receptor [24].
  • The role of the chemokine binding stromal-derived factor 1 (SDF-1) in normal human megakaryopoiesis at the cellular and molecular levels and its comparison with that of thrombopoietin (TPO) have not been determined [25].
  • Additionally, TPO-induced the tyrosine phosphorylation and DNA-binding activity of STAT3 [26].
 

Enzymatic interactions of THPO

 

Regulatory relationships of THPO

  • Inhibition of TPO-induced MEK or mTOR activity induces opposite effects on the ploidy of human differentiating megakaryocytes [27].
  • In a serum-free liquid culture, thrombopoietin (TPO) selectively stimulated the growth of megakaryocytic cells from CD34-positive cord blood cells [28].
  • The abolishment of NF-E2 p45 with NF-E2 antisense oligomers inhibited TPO plus K252a-induced polyploidization [23].
  • It is noteworthy that the differentiative effect of EPO in TF-1/c-mpl cells was associated with an increase in GATA-1 transcripts which was totally suppressed by TPO [29].
  • Inhibition of erythroid differentiation and induction of megakaryocytic differentiation by thrombopoietin are regulated by two different mechanisms in TPO-dependent UT-7/c-mpl and TF-1/c-mpl cell lines [29].
 

Other interactions of THPO

  • Furthermore, when UT-7/EPO-Mpl cells, which stably express human C-myeloproliferative leukemia virus ligand (c-Mpl), were treated with TPO, demethylation of the GP6 promoter was induced [16].
  • Altogether, our results are in line with a model in which binding of TPO to the TPO receptor (mpl) could activate the rapamycin-sensitive PI3K-AKT-mTOR-p70S6K pathway and its downstream targets in promoting megakaryocytic cell polyploidization [27].
  • The expansion efficiency (EE) of FL for each progenitor was inferior to that of SCF in the presence of various cytokines, except TPO [19].
  • We cultured these cells long term (> 6 months) in the continuous presence of TPO (omitting GM-CSF) [30].
  • Our results are consistent with previous mechanistic studies and suggest that TPO and IL-6 may be active mediators of platelet production [31].
 

Analytical, diagnostic and therapeutic context of THPO

  • The median value of TPO in AML/MDS patients during diagnosis was 150.6 pg/ml and increased significantly during chemotherapy (median: 828 pg/ml; p < 0.05) but then decreased following complete remission (median: 221.4 pg/ml) [31].
  • To evaluate hematopoiesis-supporting activity, CB CD34+ cells were expanded in cocultures with USSC and BMMSC or in the presence of Flt3-L, SCF, and TPO [32].
  • In order to test the hypothesis that c-mpl, c-mpl ligand pathway is involved in the spontaneous growth of megakaryocyte progenitors, we investigated mRNA expressions of c-mpl and TPO in cells grown in serum-free liquid culture using RT-PCR [33].
  • The effect of TPO on platelet function, both alone and in combination with other hematopoietic growth factors, adenosine diphosphate (ADP), and epinephrine, was investigated using fluorescent-labeled antibodies to the activation-dependent antigen CD62 (P-selectin) and flow cytometry [34].
  • A human TPO cDNA was isolated by PCR from kidney mRNA [35].

References

  1. The biologic properties of recombinant human thrombopoietin in the proliferation and megakaryocytic differentiation of acute myeloblastic leukemia cells. Matsumura, I., Kanakura, Y., Kato, T., Ikeda, H., Horikawa, Y., Ishikawa, J., Kitayama, H., Nishiura, T., Tomiyama, Y., Miyazaki, H., Matsuzawa, Y. Blood (1996) [Pubmed]
  2. Effects of thrombopoietin, interleukin-3 and the kinase inhibitor K-252a on growth and polyploidization of the megakaryocytic cell line M-07e. Quentmeier, H., Zaborski, M., Drexler, H.G. Leukemia (1998) [Pubmed]
  3. Pharmacologic treatment options in patients with thrombocytopenia. Demetri, G.D. Semin. Hematol. (2000) [Pubmed]
  4. Thrombopoietin production in human hepatic cell cultures (HepG2) is resistant to IFN-alpha, IFN-beta, and IFN-gamma treatment. Wolber, E.M., Haase, B., Jelkmann, W. J. Interferon Cytokine Res. (2002) [Pubmed]
  5. Thrombocytosis in preterm infants: a possible involvement of thrombopoietin receptor gene expression. Nakayama, H., Ihara, K., Hikino, S., Yamamoto, J., Nagatomo, T., Takemoto, M., Hara, T. J. Mol. Med. (2005) [Pubmed]
  6. An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia. Wiestner, A., Schlemper, R.J., van der Maas, A.P., Skoda, R.C. Nat. Genet. (1998) [Pubmed]
  7. Effects of polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor on platelet counts after chemotherapy for lung cancer. Fanucchi, M., Glaspy, J., Crawford, J., Garst, J., Figlin, R., Sheridan, W., Menchaca, D., Tomita, D., Ozer, H., Harker, L. N. Engl. J. Med. (1997) [Pubmed]
  8. Activity at the GABA transporter contributes to acute cellular swelling produced by metabolic impairment in retina. Zeevalk, G.D., Nicklas, W.J. Vision Res. (1997) [Pubmed]
  9. A novel thrombopoietin signaling defect in polycythemia vera platelets. Moliterno, A.R., Siebel, K.E., Sun, A.Y., Hankins, W.D., Spivak, J.L. Stem Cells (1998) [Pubmed]
  10. Thrombopoietin, interleukin-6, and P-selectin at diagnosis and during post-steroid recovery period of patients with autoimmune thrombocytopenic purpura. Haznedaroglu, I.C., Büyükaşik, Y., Koşar, A., Kirazh, S., Dündar, S.V. Ann. Hematol. (1998) [Pubmed]
  11. Hypersensitivity of circulating progenitor cells to megakaryocyte growth and development factor (PEG-rHu MGDF) in essential thrombocythemia. Axelrad, A.A., Eskinazi, D., Correa, P.N., Amato, D. Blood (2000) [Pubmed]
  12. Thrombopoietin in acute liver failure. Schiødt, F.V., Balko, J., Schilsky, M., Harrison, M.E., Thornton, A., Lee, W.M. Hepatology (2003) [Pubmed]
  13. Regulation of platelet activation in vitro by the c-Mpl ligand, thrombopoietin. Chen, J., Herceg-Harjacek, L., Groopman, J.E., Grabarek, J. Blood (1995) [Pubmed]
  14. The Mpl-ligand or thrombopoietin or megakaryocyte growth and differentiative factor has both direct proliferative and differentiative activities on human megakaryocyte progenitors. Debili, N., Wendling, F., Katz, A., Guichard, J., Breton-Gorius, J., Hunt, P., Vainchenker, W. Blood (1995) [Pubmed]
  15. Modulation of megakaryocytopoiesis by thrombopoietin: the c-Mpl ligand. Banu, N., Wang, J.F., Deng, B., Groopman, J.E., Avraham, H. Blood (1995) [Pubmed]
  16. Thrombopoietin initiates demethylation-based transcription of GP6 during megakaryocyte differentiation. Kanaji, S., Kanaji, T., Jacquelin, B., Chang, M., Nugent, D.J., Komatsu, N., Moroi, M., Izuhara, K., Kunicki, T.J. Blood (2005) [Pubmed]
  17. Are interleukin-16 and thrombopoietin new tools for the in vitro generation of dendritic cells? Della Bella, S., Nicola, S., Timofeeva, I., Villa, M.L., Santoro, A., Berardi, A.C. Blood (2004) [Pubmed]
  18. Cloning and analysis of the thrombopoietin-induced megakaryocyte-specific glycoprotein VI promoter and its regulation by GATA-1, Fli-1, and Sp1. Holmes, M.L., Bartle, N., Eisbacher, M., Chong, B.H. J. Biol. Chem. (2002) [Pubmed]
  19. Thrombopoietin augments ex vivo expansion of human cord blood-derived hematopoietic progenitors in combination with stem cell factor and flt3 ligand. Ohmizono, Y., Sakabe, H., Kimura, T., Tanimukai, S., Matsumura, T., Miyazaki, H., Lyman, S.D., Sonoda, Y. Leukemia (1997) [Pubmed]
  20. Thrombopoietin regulates Bcl-xL gene expression through Stat5 and phosphatidylinositol 3-kinase activation pathways. Kirito, K., Watanabe, T., Sawada, K., Endo, H., Ozawa, K., Komatsu, N. J. Biol. Chem. (2002) [Pubmed]
  21. Oxygen tension modulates the expression of cytokine receptors, transcription factors, and lineage-specific markers in cultured human megakaryocytes. Mostafa, S.S., Papoutsakis, E.T., Miller, W.M. Exp. Hematol. (2001) [Pubmed]
  22. Glucose transport activation in human hematopoietic cells M07e is modulated by cytosolic calcium and calmodulin. Maraldi, T., Rugolo, M., Fiorentini, D., Landi, L., Hakim, G. Cell Calcium (2006) [Pubmed]
  23. Transcription factor NF-E2 is essential for the polyploidization of a human megakaryoblastic cell line, Meg-J. Kobayashi, S., Teramura, M., Ito, K., Iwabe, K., Inaba, T., Mizoguchi, H. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  24. Thrombopoietin complements G(i)- but not G(q)-dependent pathways for integrin {alpha}(IIb){beta}(3) activation and platelet aggregation. Campus, F., Lova, P., Bertoni, A., Sinigaglia, F., Balduini, C., Torti, M. J. Biol. Chem. (2005) [Pubmed]
  25. Stromal-derived factor 1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis. Majka, M., Janowska-Wieczorek, A., Ratajczak, J., Kowalska, M.A., Vilaire, G., Pan, Z.K., Honczarenko, M., Marquez, L.A., Poncz, M., Ratajczak, M.Z. Blood (2000) [Pubmed]
  26. Thrombopoietin (TPO) induces tyrosine phosphorylation and activation of STAT5 and STAT3. Bacon, C.M., Tortolani, P.J., Shimosaka, A., Rees, R.C., Longo, D.L., O'Shea, J.J. FEBS Lett. (1995) [Pubmed]
  27. Inhibition of TPO-induced MEK or mTOR activity induces opposite effects on the ploidy of human differentiating megakaryocytes. Guerriero, R., Parolini, I., Testa, U., Samoggia, P., Petrucci, E., Sargiacomo, M., Chelucci, C., Gabbianelli, M., Peschle, C. J. Cell. Sci. (2006) [Pubmed]
  28. Megakaryocytes derived from CD34-positive cord blood cells produce interleukin-8. Higuchi, T., Koike, K., Sawai, N., Mwamtemi, H.H., Takeuchi, K., Shiohara, M., Kikuchi, T., Yasui, K., Ito, S., Yamagami, O., Sasaki, Y., Okumura, N., Kato, T., Miyazaki, H., Ikeda, M., Yamada, M., Komiyama, A. Br. J. Haematol. (1997) [Pubmed]
  29. Inhibition of erythroid differentiation and induction of megakaryocytic differentiation by thrombopoietin are regulated by two different mechanisms in TPO-dependent UT-7/c-mpl and TF-1/c-mpl cell lines. Goncalves, F., Lacout, C., Féger, F., Cohen-Solal, K., Guichard, J., Cramer, E., Vainchenker, W., Duménil, D. Leukemia (1998) [Pubmed]
  30. Thrombopoietin supports the continuous growth of cytokine-dependent human leukemia cell lines. Drexler, H.G., Zaborski, M., Quentmeier, H. Leukemia (1997) [Pubmed]
  31. Circulating levels of thrombopoietic and inflammatory cytokines in patients with acute myeloblastic leukemia and myelodysplastic syndrome. Hsu, H.C., Lee, Y.M., Tsai, W.H., Jiang, M.L., Ho, C.H., Ho, C.K., Wang, S.Y. Oncology (2002) [Pubmed]
  32. Cytokine production and hematopoiesis supporting activity of cord blood-derived unrestricted somatic stem cells. Kögler, G., Radke, T.F., Lefort, A., Sensken, S., Fischer, J., Sorg, R.V., Wernet, P. Exp. Hematol. (2005) [Pubmed]
  33. Proto-oncogene c-mpl is involved in spontaneous megakaryocytopoiesis in myeloproliferative disorders. Li, Y., Hetet, G., Kiladjian, J.J., Gardin, C., Grandchamp, B., Briere, J. Br. J. Haematol. (1996) [Pubmed]
  34. Thrombopoietin is synergistic with other hematopoietic growth factors and physiologic platelet agonists for platelet activation in vitro. Wun, T., Paglieroni, T., Hammond, W.P., Kaushansky, K., Foster, D.C. Am. J. Hematol. (1997) [Pubmed]
  35. Human thrombopoietin: gene structure, cDNA sequence, expression, and chromosomal localization. Foster, D.C., Sprecher, C.A., Grant, F.J., Kramer, J.M., Kuijper, J.L., Holly, R.D., Whitmore, T.E., Heipel, M.D., Bell, L.A., Ching, A.F. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
 
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