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. 1995 Sep;96(3):1683–1687. doi: 10.1172/JCI118210

Thrombopoietin expands erythroid progenitors, increases red cell production, and enhances erythroid recovery after myelosuppressive therapy.

K Kaushansky 1, V C Broudy 1, A Grossmann 1, J Humes 1, N Lin 1, H P Ren 1, M C Bailey 1, T Papayannopoulou 1, J W Forstrom 1, K H Sprugel 1
PMCID: PMC185797  PMID: 7657840

Abstract

Thrombopoietin (TPO), the ligand for the receptor protooncogene c-mpl, has been cloned and shown to be the critical regulator of platelet production. Several features of c-Mpl expression, including its presence on erythroid cell lines, and the panmyeloid transformation characteristic of myeloproliferative leukemia (MPL) viral disease led us to investigate whether this receptor-ligand system may play a role in erythropoiesis. We report that although TPO alone did not support the growth of either early or late erythroid progenitors, it acted in synergy with erythropoietin to expand these populations. Moreover, while the effects on erythropoiesis in normal animals were modest, TPO greatly expanded the number of erythroid progenitors and blood reticulocytes and was associated with accelerated red cell recovery in myelosuppressed mice. Together, these data strongly suggest that erythroid progenitors respond to TOP and that this newly cloned cytokine, critical for platelet production, can augment erythropoiesis in states of marrow failure.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andrews R. G., Knitter G. H., Bartelmez S. H., Langley K. E., Farrar D., Hendren R. W., Appelbaum F. R., Bernstein I. D., Zsebo K. M. Recombinant human stem cell factor, a c-kit ligand, stimulates hematopoiesis in primates. Blood. 1991 Oct 15;78(8):1975–1980. [PubMed] [Google Scholar]
  2. Bartley T. D., Bogenberger J., Hunt P., Li Y. S., Lu H. S., Martin F., Chang M. S., Samal B., Nichol J. L., Swift S. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell. 1994 Jul 1;77(7):1117–1124. doi: 10.1016/0092-8674(94)90450-2. [DOI] [PubMed] [Google Scholar]
  3. Birgegård G., Wide L., Simonsson B. Marked erythropoietin increase before fall in Hb after treatment with cytostatic drugs suggests mechanism other than anaemia for stimulation. Br J Haematol. 1989 Jul;72(3):462–466. doi: 10.1111/j.1365-2141.1989.tb07733.x. [DOI] [PubMed] [Google Scholar]
  4. Broudy V. C., Tait J. F., Powell J. S. Recombinant human erythropoietin: purification and analysis of carbohydrate linkage. Arch Biochem Biophys. 1988 Sep;265(2):329–336. doi: 10.1016/0003-9861(88)90135-x. [DOI] [PubMed] [Google Scholar]
  5. Broxmeyer H. E., Williams D. E., Cooper S., Shadduck R. K., Gillis S., Waheed A., Urdal D. L., Bicknell D. C. Comparative effects in vivo of recombinant murine interleukin 3, natural murine colony-stimulating factor-1, and recombinant murine granulocyte-macrophage colony-stimulating factor on myelopoiesis in mice. J Clin Invest. 1987 Mar;79(3):721–730. doi: 10.1172/JCI112877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dessypris E., Graber S. E., Krantz S. B., Stone W. J. Effects of recombinant erythropoietin on the concentration and cycling status of human marrow hematopoietic progenitor cells in vivo. Blood. 1988 Dec;72(6):2060–2062. [PubMed] [Google Scholar]
  7. Du X. X., Keller D., Maze R., Williams D. A. Comparative effects of in vivo treatment using interleukin-11 and stem cell factor on reconstitution in mice after bone marrow transplantation. Blood. 1993 Aug 1;82(3):1016–1022. [PubMed] [Google Scholar]
  8. Du X. X., Williams D. A. Interleukin-11: a multifunctional growth factor derived from the hematopoietic microenvironment. Blood. 1994 Apr 15;83(8):2023–2030. [PubMed] [Google Scholar]
  9. Emerson S. G., Sieff C. A., Wang E. A., Wong G. G., Clark S. C., Nathan D. G. Purification of fetal hematopoietic progenitors and demonstration of recombinant multipotential colony-stimulating activity. J Clin Invest. 1985 Sep;76(3):1286–1290. doi: 10.1172/JCI112087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Emerson S. G., Yang Y. C., Clark S. C., Long M. W. Human recombinant granulocyte-macrophage colony stimulating factor and interleukin 3 have overlapping but distinct hematopoietic activities. J Clin Invest. 1988 Oct;82(4):1282–1287. doi: 10.1172/JCI113727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gillio A. P., Gasparetto C., Laver J., Abboud M., Bonilla M. A., Garnick M. B., O'Reilly R. J. Effects of interleukin-3 on hematopoietic recovery after 5-fluorouracil or cyclophosphamide treatment of cynomolgus primates. J Clin Invest. 1990 May;85(5):1560–1565. doi: 10.1172/JCI114605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Girasole G., Passeri G., Jilka R. L., Manolagas S. C. Interleukin-11: a new cytokine critical for osteoclast development. J Clin Invest. 1994 Apr;93(4):1516–1524. doi: 10.1172/JCI117130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Guilbert L. J., Stanley E. R. Specific interaction of murine colony-stimulating factor with mononuclear phagocytic cells. J Cell Biol. 1980 Apr;85(1):153–159. doi: 10.1083/jcb.85.1.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gurney A. L., Carver-Moore K., de Sauvage F. J., Moore M. W. Thrombocytopenia in c-mpl-deficient mice. Science. 1994 Sep 2;265(5177):1445–1447. doi: 10.1126/science.8073287. [DOI] [PubMed] [Google Scholar]
  15. Hermine O., Beru N., Pech N., Goldwasser E. An autocrine role for erythropoietin in mouse hematopoietic cell differentiation. Blood. 1991 Nov 1;78(9):2253–2260. [PubMed] [Google Scholar]
  16. Hill R. J., Levin J. Regulators of thrombopoiesis: their biochemistry and physiology. Blood Cells. 1989;15(1):141–166. [PubMed] [Google Scholar]
  17. Ikebuchi K., Clark S. C., Ihle J. N., Souza L. M., Ogawa M. Granulocyte colony-stimulating factor enhances interleukin 3-dependent proliferation of multipotential hemopoietic progenitors. Proc Natl Acad Sci U S A. 1988 May;85(10):3445–3449. doi: 10.1073/pnas.85.10.3445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ishibashi T., Koziol J. A., Burstein S. A. Human recombinant erythropoietin promotes differentiation of murine megakaryocytes in vitro. J Clin Invest. 1987 Jan;79(1):286–289. doi: 10.1172/JCI112796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kaushansky K., Lok S., Holly R. D., Broudy V. C., Lin N., Bailey M. C., Forstrom J. W., Buddle M. M., Oort P. J., Hagen F. S. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature. 1994 Jun 16;369(6481):568–571. doi: 10.1038/369568a0. [DOI] [PubMed] [Google Scholar]
  20. Kaushansky K., O'Hara P. J., Berkner K., Segal G. M., Hagen F. S., Adamson J. W. Genomic cloning, characterization, and multilineage growth-promoting activity of human granulocyte-macrophage colony-stimulating factor. Proc Natl Acad Sci U S A. 1986 May;83(10):3101–3105. doi: 10.1073/pnas.83.10.3101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kaushansky K., Shoemaker S. G., Broudy V. C., Lin N. L., Matous J. V., Alderman E. M., Aghajanian J. D., Szklut P. J., VanDyke R. E., Pearce M. K. Structure-function relationships of interleukin-3. An analysis based on the function and binding characteristics of a series of interspecies chimera of gibbon and murine interleukin-3. J Clin Invest. 1992 Nov;90(5):1879–1888. doi: 10.1172/JCI116065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kindler V., Thorens B., de Kossodo S., Allet B., Eliason J. F., Thatcher D., Farber N., Vassalli P. Stimulation of hematopoiesis in vivo by recombinant bacterial murine interleukin 3. Proc Natl Acad Sci U S A. 1986 Feb;83(4):1001–1005. doi: 10.1073/pnas.83.4.1001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Koury M. J., Bondurant M. C. Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells. Science. 1990 Apr 20;248(4953):378–381. doi: 10.1126/science.2326648. [DOI] [PubMed] [Google Scholar]
  24. Lee M., Durch S., Dale D., Finch C. Kinetics of tumor-induced murine neutrophilia. Blood. 1979 Apr;53(4):619–632. [PubMed] [Google Scholar]
  25. Leonard J. P., Quinto C. M., Kozitza M. K., Neben T. Y., Goldman S. J. Recombinant human interleukin-11 stimulates multilineage hematopoietic recovery in mice after a myelosuppressive regimen of sublethal irradiation and carboplatin. Blood. 1994 Mar 15;83(6):1499–1506. [PubMed] [Google Scholar]
  26. Liggett W., Jr, Shevde N., Anklesaria P., Sohoni S., Greenberger J., Glowacki J. Effects of macrophage colony stimulating factor and granulocyte-macrophage colony stimulating factor on osteoclastic differentiation of hematopoietic progenitor cells. Stem Cells. 1993 Sep;11(5):398–411. doi: 10.1002/stem.5530110507. [DOI] [PubMed] [Google Scholar]
  27. 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. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature. 1994 Jun 16;369(6481):565–568. doi: 10.1038/369565a0. [DOI] [PubMed] [Google Scholar]
  28. Long M. W., Heffner C. H., Williams J. L., Peters C., Prochownik E. V. Regulation of megakaryocyte phenotype in human erythroleukemia cells. J Clin Invest. 1990 Apr;85(4):1072–1084. doi: 10.1172/JCI114538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mangan K. F., Mullaney M. T., Barrientos T. D., Kernan N. A. Serum interleukin-3 levels following autologous or allogeneic bone marrow transplantation: effects of T-cell depletion, blood stem cell infusion, and hematopoietic growth factor treatment. Blood. 1993 Apr 1;81(7):1915–1922. [PubMed] [Google Scholar]
  30. Martin D. I., Zon L. I., Mutter G., Orkin S. H. Expression of an erythroid transcription factor in megakaryocytic and mast cell lineages. Nature. 1990 Mar 29;344(6265):444–447. doi: 10.1038/344444a0. [DOI] [PubMed] [Google Scholar]
  31. McDonald T. P., Clift R. E., Cottrell M. B. Large, chronic doses of erythropoietin cause thrombocytopenia in mice. Blood. 1992 Jul 15;80(2):352–358. [PubMed] [Google Scholar]
  32. McDonald T. P., Sullivan P. S. Megakaryocytic and erythrocytic cell lines share a common precursor cell. Exp Hematol. 1993 Sep;21(10):1316–1320. [PubMed] [Google Scholar]
  33. McDonald T. P. Thrombopoietin: its biology, purification, and characterization. Exp Hematol. 1988 Mar;16(3):201–205. [PubMed] [Google Scholar]
  34. Messner H. A., Yamasaki K., Jamal N., Minden M. M., Yang Y. C., Wong G. G., Clark S. C. Growth of human hemopoietic colonies in response to recombinant gibbon interleukin 3: comparison with human recombinant granulocyte and granulocyte-macrophage colony-stimulating factor. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6765–6769. doi: 10.1073/pnas.84.19.6765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Metcalf D. Hematopoietic regulators: redundancy or subtlety? Blood. 1993 Dec 15;82(12):3515–3523. [PubMed] [Google Scholar]
  36. Migliaccio G., Migliaccio A. R., Valinsky J., Langley K., Zsebo K., Visser J. W., Adamson J. W. Stem cell factor induces proliferation and differentiation of highly enriched murine hematopoietic cells. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7420–7424. doi: 10.1073/pnas.88.16.7420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Pojda Z., Tsuboi A. In vivo effects of human recombinant interleukin 6 on hemopoietic stem and progenitor cells and circulating blood cells in normal mice. Exp Hematol. 1990 Oct;18(9):1034–1037. [PubMed] [Google Scholar]
  38. Pollard J. W., Bartocci A., Arceci R., Orlofsky A., Ladner M. B., Stanley E. R. Apparent role of the macrophage growth factor, CSF-1, in placental development. Nature. 1987 Dec 3;330(6147):484–486. doi: 10.1038/330484a0. [DOI] [PubMed] [Google Scholar]
  39. Romeo P. H., Prandini M. H., Joulin V., Mignotte V., Prenant M., Vainchenker W., Marguerie G., Uzan G. Megakaryocytic and erythrocytic lineages share specific transcription factors. Nature. 1990 Mar 29;344(6265):447–449. doi: 10.1038/344447a0. [DOI] [PubMed] [Google Scholar]
  40. Rowley P. T., Farley B. A., LaBella S., Giuliano R., Leary J. F. Single K562 human leukemia cells express and are inducible for both erythroid and megakaryocytic antigens. Int J Cell Cloning. 1992 Jul;10(4):232–240. doi: 10.1002/stem.5530100406. [DOI] [PubMed] [Google Scholar]
  41. Sanderson C. J. Interleukin-5, eosinophils, and disease. Blood. 1992 Jun 15;79(12):3101–3109. [PubMed] [Google Scholar]
  42. Sato T., Fuse A., Eguchi M., Hayashi Y., Ryo R., Adachi M., Kishimoto Y., Teramura M., Mizoguchi H., Shima Y. Establishment of a human leukaemic cell line (CMK) with megakaryocytic characteristics from a Down's syndrome patient with acute megakaryoblastic leukaemia. Br J Haematol. 1989 Jun;72(2):184–190. doi: 10.1111/j.1365-2141.1989.tb07681.x. [DOI] [PubMed] [Google Scholar]
  43. 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 Oct 10;353(1):57–61. doi: 10.1016/0014-5793(94)01008-0. [DOI] [PubMed] [Google Scholar]
  44. Tong J., Gordon M. S., Srour E. F., Cooper R. J., Orazi A., McNiece I., Hoffman R. In vivo administration of recombinant methionyl human stem cell factor expands the number of human marrow hematopoietic stem cells. Blood. 1993 Aug 1;82(3):784–791. [PubMed] [Google Scholar]
  45. Tsukada J., Misago M., Kikuchi M., Sato T., Ogawa R., Ota T., Oda S., Morimoto I., Chiba S., Eto S. Interactions between recombinant human erythropoietin and serum factor(s) on murine megakaryocyte colony formation. Blood. 1992 Jul 1;80(1):37–45. [PubMed] [Google Scholar]
  46. Wendling F., Maraskovsky E., Debili N., Florindo C., Teepe M., Titeux M., Methia N., Breton-Gorius J., Cosman D., Vainchenker W. cMpl ligand is a humoral regulator of megakaryocytopoiesis. Nature. 1994 Jun 16;369(6481):571–574. doi: 10.1038/369571a0. [DOI] [PubMed] [Google Scholar]
  47. de Sauvage F. J., Hass P. E., Spencer S. D., Malloy B. E., Gurney A. L., Spencer S. A., Darbonne W. C., Henzel W. J., Wong S. C., Kuang W. J. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature. 1994 Jun 16;369(6481):533–538. doi: 10.1038/369533a0. [DOI] [PubMed] [Google Scholar]

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