Glucocorticoid Receptors and Glucocorticoid Resistance in Human Leukemia in Vivo and in Vitro

  • E. Brad Thompson
  • Jeffrey M. Harmon
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 196)


Clinical measurements quantitating glucocorticoid receptor sites in leukemic blasts may give useful prognostic information. In childhood ALL, where the most data is available, “high” receptor content in peripheral or marrow blasts correlated with likelihood of remission on therapy, longer durations of remission and better prognosis generally. In lymphomas and CLL as well, high receptor content correlated with likelihood of response to steroid therapy, though the number of studies is less. In AML the correlation with receptor site content is moot, and in other leukemias the reports are less complete.

A model system for childhood ALL is provided by CEM cells, a glucocorticoid sensitive human cell line from a patient with the disease. These cells have glucocorticoid receptors which must be filled by hormone for >24 hr for cell lysis to begin. Four types of glucocorticoid resistance have been identified thus far in clones of these cells. Their distinctive properties are described and their relevance to clinical situations briefly discussed.


Acute Lymphoblastic Leukemia Glucocorticoid Receptor Glutamine Synthetase Receptor Occupancy Steroid Resistance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    M. E. Wolfe, Structure-activity relationship in glucocorticoids. In: Glucocorticoid Hormone Action. J.D. Baxter & G.G. Rousseau (eds.), Springer-Verlag, Berlin, 1979, pp. 97–107.CrossRefGoogle Scholar
  2. 2.
    F. W. Ruscetti and R. C. Gallo, Human T-lymphocyte growth factor: Regulation of growth and function of T-lymphocytes. Blood 57: 379 (1981)PubMedGoogle Scholar
  3. 3.
    S. Gillis, G. R. Crabtree, and K. A. Smith, Glucocorticoidinduced inhibition of T-cell growth factor production. I. The effect on mitogen-induced lymphocyte proliferation. J. Immunol. 123: 1624 (1979).PubMedGoogle Scholar
  4. 4.
    E.-L. Larsson, Cyclosporin A and dexamethasone suppress T cell response by selectively acting at distinct sites of the triggering process. J. Immunol. 124: 2828 (1980).PubMedGoogle Scholar
  5. 5.
    S. K. Arya, F. Wong-Staal and R. C. Gallo, Dexamethasone-mediated inhibition of human T-cell growth factor and gamma interferon messenger RNA. J. Immunol. 133: 273 (1984)PubMedGoogle Scholar
  6. 6.
    G. R. Adolf and P. Swetly, Glucocorticoid hormones inhibit DNA synthesis and enhance interferon production in a human lymphoid cell line. Nature 282: 736 (1979).PubMedCrossRefGoogle Scholar
  7. 7.
    U. Zor, R. Ben-Sort, I. Maoz, D. Wallach and D. Gurari-Rotman, Inhibition by glucocorticosteroid hormones of interferon and prostaglandin E by poly (rI).poly (rC). J. Gen. Virol. 63: 359 (1982).Google Scholar
  8. 8.
    G. R. Adolf and P. Swetly, Interferon production in hematopoietic cell lines: Response to chemicals and characterization of interferons. J. Interferon Res. 2: 261 (1982).PubMedCrossRefGoogle Scholar
  9. 9.
    T. Kasahara, J. J. Hooks, S. F. Dougherty and J. J. Oppenheim, Interleukin 2-mediated immune interferon (IFN-) production by human T cells and T cell subsets. J. Immunol. 130: 1784 (1983).PubMedGoogle Scholar
  10. 10.
    R. Palacios and I. Sugarawa, Hydrocortisone abrogates proliferation of T cells in autologous mixed lymphocyte reaction by rendering the interleukin 2 producer T cells unresponsive to interleukin 1 and unable to synthesize the T-cell growth factor. Scand. J. Immunol. 15: 25 (1982).PubMedCrossRefGoogle Scholar
  11. 11.
    C. H. Sibley and K. R. Yamamoto, Mouse lymphoma cells: Mechanism of resistance of glucocorticoids. In: Glucocorticoid Hormone Action. J. D. Baxter and G. G. Rousseau, (eds.), Springer-Verlag, Berlin, 1979, Chapter 20, pp. 357–376.Google Scholar
  12. 12.
    S. Bourgeois, R. F. Newby and M. Huet, Glucocorticoid resistance in murine lymphoma and thymoma lines. Cancer Res. 38: 4279 (1978).PubMedGoogle Scholar
  13. 13.
    J. Stevens and Y. Stevens, Physicochemical differences between glucocorticoid-binding components from the corticoid-sensitive and -resistant strains of mouse lymphoma. Cancer Res. 39: 4011 (1979).PubMedGoogle Scholar
  14. 14.
    M. E. Lippman, R. H. Halterman, B. C. Leventhal, S. Perry and E. B. Thompson, Glucocorticoid-binding proteins in human acute lymphoblastic leukemic blast cells. J. Clin. Invest. 52: 1715 (1973).PubMedCrossRefGoogle Scholar
  15. 15.
    J. Wolff, C. Brubaker, M. Murphy, M. Pierce, and N. Severo, Prednisone therapy of acute childhood leukemia: Prognosis and duration of response in 330 treated patients. J. Pediatr. 70: 626 (1967).PubMedCrossRefGoogle Scholar
  16. 16.
    O. Pearson and L. Eltel, Use of pituitary adrenocorticotropic hormone (ACTH) and cortisone in lymphomas and leukemias. JAMA 144: 1349 (1950).CrossRefGoogle Scholar
  17. 17.
    M. E. Lippman, G. K. Yarbro and B. G. Leventhal, Clinical implications of glucocorticoid receptors in human leukemia. Cancer Res. 38: 4251 (1978).PubMedGoogle Scholar
  18. 18.
    F. Homo, D. Duval, J. L. Harousseau, J. P. Marie and R. Zittour, Heterogeneity of the in vitro responses to glucocorticoids in acute leukemia. Cancer Res. 40: 2601 (1980).PubMedGoogle Scholar
  19. 19.
    R. Mastrangelo, R. Malandrino, R. Riccardi, P. Longo, F. O. Ranelletti and S. Iacobelli, Clinical implications of glucocorticoid receptor studies in childhood acute lymphoblastic leukemia. Blood 56: 1036 (1980).PubMedGoogle Scholar
  20. 20.
    A. D. Ho, W. Aunstein and W. Schmid, Glucocorticoid receptors and sensitivity in leukemias. Blut 42: 183 (1981).PubMedCrossRefGoogle Scholar
  21. 21.
    M. E. Costlow, C. Pui and G. V. Dahl, Glucocorticoid receptors in childhood acute lymphoblastic leukemia. Cancer Res. 42: 4801 (1982).PubMedGoogle Scholar
  22. 22.
    P. Nanni, G. Nicoletti, G. Prodi, M. C. Galli, C. DeGiovanni, S. Grilli, P.-L Lollini, M. Gobbi, M. Cavo, and S. Tura, Glucocorticoid receptor and in vitro sensitivity to steroid hormones in human lymphoproliferative diseases and myeloid leukemia. Cancer 49: 623 (1982).PubMedCrossRefGoogle Scholar
  23. 23.
    C.-H. Pui, G. V. Dahl, G. Rivera, S. B. Murphy and M. E. Costlow, The relationship of blast cells glucocorticoid receptor levels to response to single-agent steroid trial and remission response in children with acute lymphoblastic leukemia. Leuk. Res. 8: 579 (1984).PubMedCrossRefGoogle Scholar
  24. 24.
    C. D. Bloomfield, B. A. Peterson, J. Zaleskas, G. Frizzera, K. A. Smith, L. Hilebrandt, K. Gajl-Peczalska and A. Munck, In-vitro glucocorticoid studies for predicting response to glucocorticoid therapy in adults with malignant lymphoma. The Lancet 1: 952 (1980).CrossRefGoogle Scholar
  25. 25.
    B. Terenius, B. Simonsson and K. Nilsson, Glucocorticoid receptors in chronic lymphocytic leukaemia. In: Glucocorticoid Action and Leukemia, 7th Tenovus Workshop, P. A. Bell and N. M. Borthwick (eds). Alpha Omego Publishing, Ltd., Cardiff, 1978, pp. 155–159.Google Scholar
  26. 26.
    T. J. Schmidt and E. B. Thompson, Glucocorticoid receptors and glutamine synthetase in leukemic Sezary cells. Cancer Res. 39: 376 (1979).PubMedGoogle Scholar
  27. 27.
    M. E. Lippman, S. Perry and E. B. Thompson, Glucocorticoid binding proteins in myeloblasts of acute myelogenous leukemia. Am. J. Med. 59: 224 (1975).PubMedCrossRefGoogle Scholar
  28. 28.
    S. Iacobelli, F. Ranelletti, F. O. Longo, P. Riccardi and R. Mastrangelo, Discrepancies between in vivo and in vitro effects of glucocorticoids in myelomonocytic leukemic cells with steroid receptors. Cancer Res. 38: 4257 (1978).PubMedGoogle Scholar
  29. 29.
    G. Crabtree, K. Smith and A. Munck, Glucocorticoid receptors and sensitivity of isolated human leukemia and lymphoma cells. Cancer Res. 38: 4268 (1978).PubMedGoogle Scholar
  30. 30.
    N. J. Holbrook, C. D. Bloomfield and A. Munck, Stabilization of labile glucocorticoid-receptor complexes from acute nonlymphocytic leukemia cells by a factor from chronic lymphocytic leukemia cells. Cancer Res. 44: 407 (1984).PubMedGoogle Scholar
  31. 31.
    L. Skoog, B. Nordenskjold, A. Ost, B. Andersson, R. Hast, N. Giannoulis, S. Humla, T. Hagerstrom and P. Reizenstein, Glucocorticoid receptor concentrations and terminal transferase activity as indicators of prognosis in acute nonlymphocytic leukaemia. British Med. J. 282: 1826 (1981).CrossRefGoogle Scholar
  32. 32.
    M. E. Costlow, C. Pui and G. V. Dahl, Glucocorticoid receptors in childhood acute lymphoblastic leukemia. Cancer Res. 42: 4801 (1982).PubMedGoogle Scholar
  33. 33.
    G. S. Konior, M. E. Lippman, G. E. Johnson and B. G. Leventhal, Glucocorticoid receptors in subpopulations of childhood acute lymphocytic leukemia. Cancer Res. 37: 2688 (1977).Google Scholar
  34. 34.
    M. E. Lippman, G. S. K. Yarbro and B. Leventhal, Glucocorticoid receptors in normal and leukaemic human leucocytes. In: Glucocorticoid Action and Leukaemia. Seventh Tenovus Workshop, P. A. Bell and N. M. Borthwick (eds.), Alpha Omega Publishing Ltd., Cardiff, 1978, pp. 175–190.Google Scholar
  35. 35.
    G. E. Foley, H. Lazarus, S. Farber, B. F. Uzman, B. A. Boone and R. E. McCarthy, Continuous culture of human lymphoblasts from peripheral blood of a child with acute leukemia. Cancer 18: 522 (1965).PubMedCrossRefGoogle Scholar
  36. 36.
    M. R. Norman, J. M. Harmon, and E. B. Thompson, Use of a human lymphoid cell line to evaluate interactions between prednisolone and other chemotherapeutic agents. Cancer Res. 38: 4273 (1978).PubMedGoogle Scholar
  37. 37.
    J. M. Harmon, M. R. Norman, B. J. Fowlkes and E. B. Thompson, Dexamethasone induces irreversible G, arrest and death of a human lymphoid cell line. J. Cell. Physiol. 98: 267 (1979).PubMedCrossRefGoogle Scholar
  38. 38.
    R. Zawydiwski, J. M. Harmon and E. B. Thompson, Glucocorticoidresistant human acute lymphoblastic leukemia cell line with functional receptor. Cancer Res. 43: 3865 (1983).PubMedGoogle Scholar
  39. 39.
    J. M. Harmon and E. B. Thompson, Glutamine synthetase induction by glucocorticoids in the glucocorticoid-sensitive human leukemic cell line CEM-C7. J. Cell. Physiol. 110: 155 (1982).PubMedCrossRefGoogle Scholar
  40. 40.
    E. B. Thompson, J. R. Smith, S. Bourgeois and J. M. Harmon, Glucocorticoid receptors and human leucopathic diseases. In: Proceedings of the 1983 Schering Symposium on Aspects of Research on Glucocorticoid Receptors, Graupe, K. (ed.) 1983, in press.Google Scholar
  41. 41.
    J. C. Gasson, T. Ryden, and S. Bourgeois, Role of de novo DNA methylation in the glucocorticoid resistance of a T-lymphoid cell line. Nature 302: 621 (1983).PubMedCrossRefGoogle Scholar
  42. 42.
    J. C. Gasson and S. Bourgeois, A new determinant of glucocorticoid sensitivity in lymphoid cell lines. J. Cell Biol. 96: 409 (1983).PubMedCrossRefGoogle Scholar
  43. 43.
    W. Doerfler, DNA methylation and gene activity. Ann. Rev. Biochem. 52: 93 (1983).Google Scholar
  44. 44.
    J. M. Harmon and E. B. Thompson, Isolation and characterization of dexamethasone-resistant mutants from human lymphoid cell line CEM C7. Mol. Cell. Biol. 1: 512 (1981).PubMedGoogle Scholar
  45. 45.
    Y. Sakaue and E. B. Thompson, Characterization of two forms of glucocorticoid hormone-receptor complex separated by DEAEcellulose column chromatography. Biochem. Biophys. Res. Commun. 77: 533 (1977).PubMedCrossRefGoogle Scholar
  46. 46.
    T. J. Schmidt, J. M. Harmon and E. B. Thompson, ‘Activation-labile’ glucocorticoid-receptor complexes of a steroid-resistant variant of CEM-C7 human lymphoid cells. Nature 286: 507 (1980).PubMedCrossRefGoogle Scholar
  47. 47.
    J. M. Harmon, T. J. Schmidt and E. B. Thompson, Molybdatesensitive and molybdate-resistant activation-labile glucocorticoid-receptor mutants of the human lymphoid cell line CEM-C7. J. Steroid Biochem. 21: 227 (1984).PubMedCrossRefGoogle Scholar
  48. 48.
    S. S. Simons, Jr. and E. B. Thompson, Dexamethasone-21-mesylate: an affinity label of glucocorticoid receptors from rat hepatoma tissue culture cells. Proc. Natl. Acad. Sci. USA 78: 3541 (1981).PubMedCrossRefGoogle Scholar
  49. 49.
    J. M. Harmon, H. J. Eisen, S. T. Brower, S. S. Simons, Jr., C. L. Langley and E. B. Thompson, Identification of human leukemic glucocorticoid receptors using affinity labeling and anti-human glucocorticoid receptor antibodies. Cancer Res. 44: 4540 (1984).PubMedGoogle Scholar
  50. 50.
    K. L. Leach, M. K. Dahmer, N. D. Hammond, J. J. Sando and W. B. Pratt, Molybdate inhibition of glucocorticoid receptor inactivation and transformation. J. Biol. Chem. 254: 11884 (1979)PubMedGoogle Scholar
  51. 51.
    J. M. Harmon, E. B. Thompson and K. A. Baione, Analysis of glucocorticoid-resistant human leukemic cells by somatic cell hybridization. J. Steroid Biochem., in press.Google Scholar
  52. 52.
    J. W. Littlefield, The use of drug-resistant markers to study the hybridization of mouse fibroblasts. Exptl. Cell Res. 41: 190 (1966).PubMedCrossRefGoogle Scholar
  53. 53.
    E. B. Thompson, D. K. Granner, T. Gelehrter, J. Erickson and G. L. Hager, Unlinked control of multiple glucocorticoidinduced processes in HTC cells. Mol Cell. Endocrinol. 15: 135 (1979).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • E. Brad Thompson
    • 1
  • Jeffrey M. Harmon
    • 2
  1. 1.Department of Human Biological Chemistry and GeneticsThe University of Texas Medical BranchGalvestonUSA
  2. 2.Department of PharmacologyUniformed Services University of Health SciencesBethesdaUSA

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