In Vitro

, Volume 14, Issue 1, pp 155–161

Regulation of differentiation in normal and transformed erythroid cells

  • Richard A. Rifkind
  • Paul A. Marks
  • Arthur Bank
  • Masaaiki Terada
  • Roberta C. Reuben
  • George M. Maniatis
  • Eitan Fibach
  • Uri Nudel
  • Jane E. Salmon
  • Yair Gazitt
Symposia Proceeding Mechanisms of Cellular Control

Summary

Studies are described employing two erythropoietic systems to elucidate regulatory mechanisms that control both normal erythropoiesis and erythroid differentiation of transformed hemopoietic precursors. Evidence is provided suggesting that normal erythroid cell precursors require erythropoietin as a growth factor that regulates the number of precursors capable of differentiating. Murine erythroleukemia cells proliferate without need of erythropoietin; they show a variable, generally low, rate of spontaneous differentiation and a brisk rate of erythropoiesis in response to a variety of chemical agents. Present studies suggest that these chemical inducers initiate a series of events including cell surface related changes, alterations in cell cycle kinetics, and modifications of chromatin and DNA structure which result in the irreversible commitment of these leukemia cells to erythroid differentiation and the synthesis of red-cell-specific products.

Key words

erythropoiesis Friend cell erythroleukemia erythropoietin differentiation 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Marks, P. A., and R. A. Rifkind. 1972. Control of protein synthesis in erythropoiesis. Science 175: 955–961.PubMedCrossRefGoogle Scholar
  2. 2.
    Friend, C., W. Scher, J. G. Holland,and T. Sato. 1971. Hemoglobin synthesis in murine virus induced leukemic cellsin vitro: stimulation of erythroid differentiation by dimethyl sulfoxide. Proc. Natl. Acad. Sci. U.S.A. 68: 378–382.PubMedGoogle Scholar
  3. 3.
    Tanaka, M., J. Levy, M. Terada, R. Breslow, R. A. Rifkind, and P. A. Marks. 1975. Induction of erythroid differentiation in murine virus infected erythroleukemia cells by highly polar compounds. Proc. Natl. Acad. Sci. U.S.A. 72: 1003–1006.PubMedCrossRefGoogle Scholar
  4. 4.
    Reuben, R. C., R. L. Wife, R. Breslow, R. A. Rifkind, and P. A. Marks. 1976. Identification of a new group of potent inducers of differentiation in murine erythroleukemia cells. Proc. Natl. Acad. Sci. U.S.A. 73: 862–866.PubMedCrossRefGoogle Scholar
  5. 5.
    Leder, A., and P. Leder. 1975. Butyric acid, a potent inducer of erythroid differentiation in cultured erythroleukemic cells. Cell 5: 319–322.PubMedCrossRefGoogle Scholar
  6. 6.
    Gusella, J., and D. Housman. 1976. Differentiationin vitro by purine and purine analogs. Cell 8: 263–209.PubMedCrossRefGoogle Scholar
  7. 7.
    Sugano, H., M. Furusawa, T. Kawaguchi, and Y. Ikawa. 1973. Enhancement of erythrocytic maturation of Friend virus-induced leukemia cellsin vitro. In: R. M. Duthcer, L. Chieco-Bianchi (Eds.),Unifying Concepts of Leukemia. Karger, Basel, pp. 943–954.Google Scholar
  8. 8.
    Preisler, H. D., G. Christoff, and E. Taylor. 1976. Cryoprotective agents as inducers of erythroleukemic cell differentiationin vitro. Blood 47: 363–368.PubMedGoogle Scholar
  9. 9.
    Ross, J., and D. Sautner. 1976. Induction of globin mRNA accumulation by hemin in cultured erythroleukemic cells. Cell 8: 513–520.PubMedCrossRefGoogle Scholar
  10. 10.
    Ebert, P. S., I. Wars, and D. N. Buell. 1976. Erythroid differentiation in cultured Friend leukemia cells treated with metabolic inhibitors. Cancer Res. 36: 1809–1813.PubMedGoogle Scholar
  11. 11.
    Chui, D. H. K., M. Djaldetti, P. A. Marks, and R. A. Rifkind. 1971. Erythropoietin effects on fetal mouse erythroid cells, I. Cell population and hemoglobin synthesis. J. Cell Biol. 51: 585–595.PubMedCrossRefGoogle Scholar
  12. 12.
    Cantor, L. N., A. J. Morris, P. A. Marks, and R. A. Rifkind. 1972. Purification of the erythropoietin-responsive cell by immune hemolysis. Proc. Natl. Acad. Sci. U.S.A. 69: 1337–1341.PubMedCrossRefGoogle Scholar
  13. 13.
    Cooper, M., J. Levy, L. N. Cantor, P. A. Marks, and R. A. Rifkind. 1974. The effect of erythropoietin on colonial growth of erythroid precursor cellsin vitro. Proc. Natl. Acad. Sci. U.S.A. 71: 1677–1680.PubMedCrossRefGoogle Scholar
  14. 14.
    Djaldetti, M., H. Preisler, P. A. Marks, and R. A. Rifkind. 1972. Erythropoietin effects on fetal mouse erythroid cells. II. Nucleic acid synthesis and the erythropoietin-sensitive cell. J. Biol. Chem. 247: 731–735.Google Scholar
  15. 15.
    Ramirez, R., R. Gambino, G. M. Maniatis, R. A. Rifkind, P. A. Marks, and A. Bank. 1975. Changes in globin messenger RNA content during erythroid cell differentiation. J. Biol. Chem. 250: 6054–6058.PubMedGoogle Scholar
  16. 16.
    Terada, M., L. Cantor, R. A. Rifkind, A. Bank, and P. A. Marks. 1972. Globin mRNA activity in erythroid precursor cells and the effect of erythropoietin. Proc. Natl. Acad. Sci. 69: 3575–3579.PubMedCrossRefGoogle Scholar
  17. 17.
    Maniatis, G. M., R. A. Rifkind, A. Bank, and P. A. Marks. 1973. Early stimulation of RNA synthesis by erythropoietin in cultured of erythroid precursor cells. Proc. Natl. Acad. Sci. 70: 3189–3194.PubMedCrossRefGoogle Scholar
  18. 18.
    Rifkind, R. A., P. A. Marks, A. Bank, M. Terada, G. M. Maniatis, R. Reuben, and E. Fibach. 1976. Erythroid differentiation and the cell cycle: some implications from murine fetal and erythroleukemic cells. Ann. Immunol. (Paris) 127: 887–893.Google Scholar
  19. 19.
    Weintraub, H. 1975. The organization of red cell differentiation, in cell cycle and cell differentiation. In: J. Reinert, and H. Holtzer (Eds.), Results and Problems— Cell Differentiation. Vol. 7. Springer-Verlag, New York, pp. 27–42.Google Scholar
  20. 20.
    Singer, D., M. Cooper, G. M. Maniatis, P. A. Marks, and R. A. Rifkind. 1974. Erythropoietic differentiation in colonies of Friend virus transformed cells. Proc. Natl. Acad. Sci. U.S.A. 71: 2668–2670.PubMedCrossRefGoogle Scholar
  21. 21.
    Sato, R., C. Friend, and E. de Harven. 1971. Ultrastructural changes in Friend erythroleukemia cells treated with dimethylsulfoxide. Cancer Res. 31: 1402–1417.PubMedGoogle Scholar
  22. 22.
    Ross, J., Y. Ikawa, and P. Leder. 1972. Globin messenger-RNA induction during erythroid differentiation of cultured leukemia cells. Proc. Natl. Acad. Sci. U.S.A. 69: 3620–3623.PubMedCrossRefGoogle Scholar
  23. 23.
    Ostertag, W., H. Melderis, G. Steinheider, N. Kluge, and S. K. Dube. 1972. Synthesis of mouse hemoglobin and globin mRNA in leukemic cell cultures. Nature [New Biol.] 239: 231–234.Google Scholar
  24. 24.
    Gilmour, R. A., P. R. Harrison, J. D. Windass, N. A. Affara, and J. Paul. 1974. Globin messenger RNA synthesis and processing during hemoglobin induction in Friend cells. I. Evidence for transcriptional control in clone M2. Cell Differ. 3: 9–22.PubMedCrossRefGoogle Scholar
  25. 25.
    Boyer, S. H., K. D. Wuu, A. N. Noyes, R. Young, W. Scher, C. Friend, H. D. Preisler, and A. Bank. 1972. Hemoglobin biosynthesis in murine virus-induced leukemic cellsin vitro: structure and amounts of globin chains produced. Blood 40: 823–835.PubMedGoogle Scholar
  26. 26.
    Ebert, P. S., and Y. Ikawa. 1974. Induction of δ-aminolevulinic acid synthetase during erythroid differentiation of cultured leukemia cells. Proc. Soc. Exp. Biol. Med. 146: 601–604.PubMedGoogle Scholar
  27. 27.
    Kabat, D., C. C. Sherton, L. H. Evans, R. Bigley, and R. D. Koler. 1975. Synthesis of erythrocytespecific proteins in cultured Friend leukemia cells. Cell 5: 331–338.PubMedCrossRefGoogle Scholar
  28. 28.
    Furusawa, M., Y. Ikawa, and H. Sugano. 1971. Development of erythrocyte membrane-specific antigen(s) in clonal cultured cells of Friend virus-induced tumor. Proc. Jpn. Acad. 47: 220–224.Google Scholar
  29. 29.
    Fibach, E., R. C. Reuben, R. A. Rifkind, P. A. Marks. 1977. Effect of hexamethylene bisacetamide on the commitment to differentiation of murine erythroleukemia cells. Cancer Res. 37: 440–444.PubMedGoogle Scholar
  30. 30.
    Ohta, Y., M. Tanaka, O. J. Miller, A. Bank, P. A. Marks, and R. A. Rifkind. 1976. Erythroid cell differentiation: murine erythroleukemia cell variant with unique pattern of induction by polar compounds. Proc. Natl. Acad. Sci. U.S.A. 73: 1232–1236.PubMedCrossRefGoogle Scholar
  31. 31.
    Paul, J., and I. Hickey. 1974. Hemoglobin synthesis in inducible, uninducible and hybrid Friend cell clones. Exp. Cell Res. 87: 20–30.PubMedCrossRefGoogle Scholar
  32. 32.
    Ikawa, Y., M. Aida, and Y. Inoue. 1976. Isolation and characterization of high and low differentiation-inducible Friend leukemia lines. Gann 67: 767–770.PubMedGoogle Scholar
  33. 33.
    Rovera, G., and J. Bonaiuto. 1976. The phenotypes of variant clones of Friend mouse erythroleukemic cells resistant to dimetylsulfoxide. Cancer Res. 36: 4057–4061.PubMedGoogle Scholar
  34. 34.
    Mirand, E. A. 1972. Erythropoietin-independent erythropoiesis induced by a virus. Regulation of erythropoiesis. 1st International Conference on hematopoiesis (Eds. A. S. Gordon, M. Condorelli, and C. Peschle). Milan, Il Ponte. pp. 333–341.Google Scholar
  35. 35.
    Liao, S. K., and A. A. Axelrad. 1975. Erythropoietin-independent erythroid colony formationin vitro by hemopoietic cells of mice infected with Friend virus. Int. J. Cancer 15: 467–482.PubMedCrossRefGoogle Scholar
  36. 36.
    Reuben, R. C., R. A. Rifkind, and P. A. Marks. 1977. Murine erythroleukemia: induction to erythroid differentiation with hexamethylene bisacetamide. Fed. Proc. 36: 886.Google Scholar
  37. 37.
    Dube, S. K., G. Gaedick, N. Kluge, B. J. Weismann, H. Melderis, G. Steinheider, T. Crozier, H. Beckman, and W. Ostertag. 1974. Hemoglobin synthesizing mouse and human erythroleukemic cell lines as model systems for the study of differentiation and control of gene expression. Proceedings of the 4th International Symposium of the Princess Takamatsu Cancer Research Fund. Univ. Park Press, Tokyo, pp. 99–132.Google Scholar
  38. 38.
    Eisen, H., S. Nasi, C. P. Georgopoulos, D. Arndt-Jovin, W. Ostertag. 1977. Surface changes in differentiating Friend erythroleukemic cells in culture. Cell 10: 689–695.PubMedCrossRefGoogle Scholar
  39. 39.
    Rovera, G., T. A. O'Brien, L. Diamond. 1977. Tumor promoters inhibit spontaneous differentiation of Friend erythroleukemia cells in culture. Proc. Natl. Acad. Sci. U.S.A. 74: 2894–2898.PubMedCrossRefGoogle Scholar
  40. 40.
    Yamasaki, H., E. Fibach, U. Nudel, I. B. Weinstein, R. A. Rifkind, and P. A. Marks. 1977. Tumor promoters inhibit spontaneous and induced differentiation of murine erythroleukemia cells in culture. Proc. Nat. Acad. Sci. U.S.A. 74: 3451–3455.CrossRefGoogle Scholar
  41. 41.
    Kubinski, H., M. A. Strangstelien, W. M. Baird, and R. F. Boutwell. 1973. Interactions of phorbol esters with cellular membranesin vitro. Cancer Res. 33: 3103–3107.PubMedGoogle Scholar
  42. 42.
    Jacobson, K., C. E. Wenner, G. Kemp, and D. Papahadjopoulos. 1975. Surface properties of phorbol esters and their interaction with lipid monolayers and bilayers. Cancer Res. 35: 2991–2995.PubMedGoogle Scholar
  43. 43.
    Lyman, G. H., D. Papahadjopoulos, and H. D. Preisler. 1976. Phospholipid membrane stabilization by dimethylsulfoxide and other inducers of Friend leukemic cell differentiation. Biochim. Biophys. Acta. 448: 460–473.PubMedCrossRefGoogle Scholar
  44. 44.
    Holtzer, H., H. Weintraub, R. Mayne, and B. Mochan. 1973. The cell cycle, cell lineages and cell differenation. Curr. Top. Dev. Biol. 7: 229–256.CrossRefGoogle Scholar
  45. 45.
    Rutter, W. J., R. L. Pictet, and P. W. Morris. 1973. Toward molecular mechanisms of developmental processes. Annu. Rev. Biochem. 42: 601–646.PubMedCrossRefGoogle Scholar
  46. 46.
    Levy, J., M. Terada, R. A. Rifkind, and P. A. Marks. 1975. Induction of erythroid differentiation in Friend virus infected cells by dimethylsulfoxide: relationship to the cell cycle. Proc. Natl. Acad. Sci. U.S.A. 72: 28–32.PubMedCrossRefGoogle Scholar
  47. 47.
    McClintock, P. R., and J. Papaconstantinou. 1974. Regulation of hemoglobin synthesis in a murine erythroblastic leukemic cell: the requirement for replication to induce hemoglobin synthesis. Proc. Natl. Acad. Sci. U.S.A. 71: 4551–4555.PubMedCrossRefGoogle Scholar
  48. 48.
    Terada, M., J. Friend, U. Nudel, R. A. Rifkind, and P. A. Marks. 1977. Transient inhibition of initiation of S-phase associated with induction of murine erythroleukemia cells to erythroid differentiation by dimethylsulfoxide. Proc. Natl. Acad. Sci. U.S.A. 74: 248–252.PubMedCrossRefGoogle Scholar
  49. 49.
    Terada, M., Y. Ohta, U. Nudel, R. A. Rifkind, and P. A. Marks. 1977. Changes in DNA associated with induction of murine erythroleukemia cells to erythroid differentiation. Proc. Amer. Assoc. Cancer Res. 18: 23.Google Scholar
  50. 50.
    Gusella, J., R. Geller, B. Clarke, V. Weeks, and D. Housman. 1976. Commitment to erythroid differentiation by Friend erythroid leukemia cells: a stochiastic analysis. Cell 9: 221–229.PubMedCrossRefGoogle Scholar
  51. 51.
    Hutton, J. J., J. Bishop, R. Schweet, and E. S. Russell. 1962. Hemoglobin inheritance in inbred mouse strains. I. Structural differences. Proc. Natl. Acad. Sci. U.S.A. 48: 1505–1513.PubMedCrossRefGoogle Scholar
  52. 52.
    Gilman, J. 1976. Mouse hemoglobin beta chains: sequence data on embryonic y chain and genetic linkage of the y-chain locus to the adult β-chain locus hbb. Biochem. J. 155: 231–241.PubMedGoogle Scholar
  53. 53.
    Gilman, J. 1976. Mouse hemoglobin beta chains: comparative sequence data on adult major and minor beta chains from two species, Mus Musculus and Mus Cervicolor. Biochem. J. 159: 43–53.PubMedGoogle Scholar
  54. 54.
    Nudel, U., J. D. Salmon, M. Terada, A. Bank, R. A. Rifkind, and P. A. Marks. 1977. Differential effects of chemical inducers on the expression of β globin genes in murine erythroleukemia cells. Proc. Natl. Acad. Sci. U.S.A. 74: 1100–1104.PubMedCrossRefGoogle Scholar

Copyright information

© Tissue Culture Association 1977

Authors and Affiliations

  • Richard A. Rifkind
    • 1
  • Paul A. Marks
    • 1
  • Arthur Bank
    • 1
  • Masaaiki Terada
    • 1
  • Roberta C. Reuben
    • 1
  • George M. Maniatis
    • 1
  • Eitan Fibach
    • 1
  • Uri Nudel
    • 1
  • Jane E. Salmon
    • 1
  • Yair Gazitt
    • 1
  1. 1.College of Physicians and SurgeonsColumbia UniversityNew York
  2. 2.Columbia Presbyterian Medical CenterNew York

Personalised recommendations