Skip to main content
SpringerLink
Log in

Regulation of differentiation in normal and transformed erythroid cells

  • Symposia Proceeding
  • Mechanisms of Cellular Control
  • Published:
In Vitro Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Marks, P. A., and R. A. Rifkind. 1972. Control of protein synthesis in erythropoiesis. Science 175: 955–961.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  5. Leder, A., and P. Leder. 1975. Butyric acid, a potent inducer of erythroid differentiation in cultured erythroleukemic cells. Cell 5: 319–322.

    Article  PubMed  CAS  Google Scholar 

  6. Gusella, J., and D. Housman. 1976. Differentiationin vitro by purine and purine analogs. Cell 8: 263–209.

    Article  PubMed  CAS  Google Scholar 

  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. Preisler, H. D., G. Christoff, and E. Taylor. 1976. Cryoprotective agents as inducers of erythroleukemic cell differentiationin vitro. Blood 47: 363–368.

    PubMed  CAS  Google Scholar 

  9. Ross, J., and D. Sautner. 1976. Induction of globin mRNA accumulation by hemin in cultured erythroleukemic cells. Cell 8: 513–520.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  21. Sato, R., C. Friend, and E. de Harven. 1971. Ultrastructural changes in Friend erythroleukemia cells treated with dimethylsulfoxide. Cancer Res. 31: 1402–1417.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  31. Paul, J., and I. Hickey. 1974. Hemoglobin synthesis in inducible, uninducible and hybrid Friend cell clones. Exp. Cell Res. 87: 20–30.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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. 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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  45. Rutter, W. J., R. L. Pictet, and P. W. Morris. 1973. Toward molecular mechanisms of developmental processes. Annu. Rev. Biochem. 42: 601–646.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. College of Physicians and Surgeons, Columbia University, 10032, New York, New York

    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

Authors
  1. Richard A. Rifkind
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul A. Marks
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arthur Bank
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masaaiki Terada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Roberta C. Reuben
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. George M. Maniatis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eitan Fibach
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Uri Nudel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jane E. Salmon
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yair Gazitt
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

These studies were supported in part by grants and contracts from the National Institutes of Health (GM-14552, CA-13696, CA-18314, NO1-CB-4008 and NO1-CP-1008) and the National Science Foundation (NSF-PCM-75-08696). E.F. and R.C.R. are fellows of the Schultz Foundation; A.B. was supported in part as an American Cancer Society Scholar; J.E.S. was supported by a USPHS Medical Scientist Training Grant; and M.T. and G.M.M. are Hirschl Trust Scholars.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rifkind, R.A., Marks, P.A., Bank, A. et al. Regulation of differentiation in normal and transformed erythroid cells. In Vitro 14, 155–161 (1978). https://doi.org/10.1007/BF02618182

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02618182

Key words

Search

Navigation