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Hematopoietic growth and differentiation factors and the reversibility of malignancy: Cell differentiation and by-passing of genetic defects in leukemia

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Our development of systems for thein vitro cloning and clonal differentiation of normal hematopoietic cells made it possible to identify: (a) the factors that regulate growth and differentiation of these normal cells; (b) the changes in the normal development program that result in leukemia, and (c) how to reverse malignancy in leukemic cells. I have mainly used myeloid cells as a model system. Normal hematopoietic cells require different proteins to induce growth (growth factors) and differentiation (differentiation factors). There is a multigene family for these factors. Identification of these factors and their interaction has shown how growth and differentiation can be normally coupled. The development of leukemia involves the uncoupling of growth and differentiation. This can occur by changing the requirement for growth without blocking cell response to the normal inducers of differentiation. Addition of normal differentiation factors to these malignant cells still induces their normal differentiation, and the mature cells are then no longer malignant. Genetic changes which inhibit differentiation by normal differentiation factors can occur in the progression of leukemia, but even these leukemic cells may still be induced to differentiate by other compounds, including low doses of compounds now being used in cancer therapy, that can induce differentiation by alternative pathways. The differentiation of leukemic to mature cells results in the reversion of malignancy by by-passing genetic changes that produce the malignant phenotype. We have obtained this differentiation of leukemic cellsin vitro andin vivo, and by-passing genetic defects by inducing differentiation can be a useful approach to therapy.

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  1. 1.

    Ginsburg H, Sachs L: Formation of pure suspension of mast cells in tissue culture by differentiation of lymphoid cells from the mouse thymus.J Natl Cancer Inst 31, 1 (1963).

  2. 2.

    Sachs L: Constitutive uncoupling of pathways of gene expression that control growth and differentiation in myeloid leukemia: a model for the origin and progression of malignancy.Proc Natl Acad Sci, USA 77, 6152 (1980).

  3. 3.

    Sachs L: Normal developmental programmes in myeloid leukaemia: regulatory proteins in the control of growth and differentiation.Cancer Surveys 1, 321 (1982).

  4. 4.

    Sachs L: Normal regulators, oncogenes and the reversibility of malignancy.Cancer Surveys 3, 210 (1984).

  5. 5.

    Sachs L: Regulators of growth, differentiation and the reversion of malignancy. Normal hematopoiesis and leukemia, in:Molecular Biology of Tumor Cells, pp. 257–280. Nobel Conference, Stockholm, New York, Raven Press (1985).

  6. 6.

    Sachs L: Growth, differentiation and the reversal of malignancy.Scient Am 254, 40 (1986).

  7. 7.

    Pluznik D H, Sachs L: The cloning of normal ‘mast’ cells in tissue culture.J Cell Comp Physiol 66, 319 (1965).

  8. 8.

    Pluznik D H, Sachs L: The induction of clones of normal ‘mast’ cells by a substance from conditioned medium.Exp Cell Res 43, 553 (1966).

  9. 9.

    Ichikawa Y, Pluznik D H, Sachs L:In vitro control of the development of macrophage and granulocyte colonies.Proc Natl Acad Sci, USA 56, 488 (1966).

  10. 10.

    Bradley T R, Metcalf D: The growth of mouse bone marrow cellsin vitro.Aust J Exp Biol Med Sci 44, 287 (1966).

  11. 11.

    Mier J W, Gallo R C: Purification and some characteristics of human T-cell growth factor from phytohemagglutinin-stimulated lymphocyte-conditioned media.Proc Natl Acad Sci, USA 77, 6134 (1980).

  12. 12.

    Möller G (ed): B cell growth and differentiation factors.Immun Rev 78 (1984).

  13. 13.

    Weisinger G, Sachs L: DNA-binding protein that induces cell differentiation.EMBO J 2, 2105 (1983).

  14. 14.

    Weisinger G, Korn A P, Sachs L: Multimeric complexes of differentiation-inducing protein bound to DNA.Eur J Cell Biol 37, 196 (1985).

  15. 15.

    Sachs L, Lotem J: Haematopoietic growth factors.Nature 312, 407 (1984).

  16. 16.

    Metcalf D: The granulocyte-macrophage colonystimulating factors.Science 299, 16 (1985).

  17. 17.

    Fung M C, Hapel S J, Ymer S, Cohen D R, Johnson R M, Campbell H D, Young I G: Molecular cloning ofcDNA for murine interleukin-3.Nature 307, 233 (1984).

  18. 18.

    Yokota T, Lee F, Rennick D, Hall C, Arai N, Mosmann T, Nabel G, Cantor H, Arai K-I: Isolation and characterization of a mousecDNA clone that expresses mast-cell growth-factor activity in monkey cells.Proc Natl Acad Sci, USA 81, 1070 (1984).

  19. 19.

    Gough N M, Gough J, Metcalf D, Kelso A, Grail D, Nicola N A, Burgess A W, Dunn A R: Molecular cloning ofcDNA encoding a murine haematopoietic growth regulator, granulocyte-macrophage colony stimulating factor.Nature 309, 763 (1984).

  20. 20.

    Kawasaki E S, Ladner M B, Wang A M, Van Arsdell J, Kim W M, Coyne M Y, Schweickart V L, Lee M-T, Wilson K J, Boosman A, Stanley E R, Ralph P, Mark D F: Molecular cloning of a complementary DNA encoding human macrophage-specific colony-stimulating factor (CSF-1).Science 230, 291 (1985).

  21. 21.

    Nagata S, Tsuchiya M, Asano S, Kaziro Y, Yamazaki T, Yamamoto O, Hirata Y, Kubota N, Oheda M, Nomura H, Ono M: Molecular cloning and expression ofcDNA for human granulocyte colonystimulating factor.Nature 319, 415 (1986).

  22. 22.

    Ichikawa Y, Maeda N, Horiuchi M:In vitro differentiation of Rauscher virus induced myeloid leukemic cells.Int J Cancer 17, 789 (1976).

  23. 23.

    Tomida M, Yamamoto-Kamaguchi Y, Hozumi M: Purification of a factor inducing differentiation of mouse myeloid leukemic M1 cells from conditioned medium from mouse fibroblast L929 cells.J Biol Chem 259, 10978 (1984).

  24. 24.

    Olsson I, Sarngadharan M G, Breitman T R, Gallo R C: Isolation and characterisation of a T lymphocyte-derived differentiation inducing factor for the myeloid leukemic cell line HL-60.Blood 63, 510 (1984).

  25. 25.

    Lotem J, Sachs L: Mechanisms that uncouple growth and differentiation in myeloid leukemia cells. Restoration of requirement for normal growthinducing protein without restoring induction of differentiation-inducing protein.Proc Natl Acad Sci, USA 79, 4347 (1982).

  26. 26.

    Lotem J, Sachs L: Coupling of growth and differentiation in normal myeloid precursors and the breakdown of this coupling in leukemia.Int J Cancer 32, 127 (1983).

  27. 27.

    Sachs L: Regulation of membrane changes, differentiation and malignancy in carcinogenesis.Harvey Lectures, Vol. 68, pp. 1–35, New York, Academic Press (1974).

  28. 28.

    Liebermann D, Hoffman-Liebermann B, Sachs L: Molecular dissection of differentiation in normal and leukemic myeloblasts: separately programmed pathways of gene expression.Devel Biol 79, 46 (1980).

  29. 29.

    Cohen L, Sachs L: Constitutive gene expression in myeloid leukemia and cell competence for induction of differentiation by the steroid dexamethasone.Proc Natl Acad Sci, USA 78, 353 (1981).

  30. 30.

    Sachs L: Control of normal cell differentiation and the phenotypic reversion of malignancy in myeloid leukemia.Nature 274, 535 (1978).

  31. 31.

    Symonds G, Sachs L: Autoinduction of differentiation in myeloid leukemic cells: restoration of normal coupling between growth and differentiation in leukemic cells that constitutively produce their own growth-inducing protein.EMBO J 1, 1343 (1982).

  32. 32.

    Tushinski R J, Oliver I T, Guilbert L J, Tynan P W, Warner J R, Stanley E R: Survival of mononuclear phagocytes depends on a lineage-specific growth factor that the differentiated cells selectively destroy.Cell 28, 71 (1982).

  33. 33.

    Wilkinson P C:Chemotaxis and Inflammation. London, Churchill Livingstone (1974).

  34. 34.

    Symonds G, Sachs L: Activation of normal genes in malignant cells: activation of chemotaxis in relation to other stages of normal differentiation in myeloid leukemia.Somat Cell Genet 5, 931 (1979).

  35. 35.

    Klein G: The role of gene dosage and genetic transposition in carcinogenesis.Nature 194, 313 (1981).

  36. 36.

    Land H, Parada L F, Weinberg R A: Cellular oncogenes and multistep carcinogenesis.Science 222, 771 (1983).

  37. 37.

    Bishop J M: Cellular oncogenes and retroviruses.Ann Rev Biochem 52, 301 (1983).

  38. 38.

    Cooper G M: Cellular transforming genes.Science 218, 801 (1982).

  39. 39.

    Temin M, Miller K: Insertion of oncogenes into retrovirus vectors.Cancer Surveys 3, 229 (1984).

  40. 40.

    Waterfield M D, Scrace G T, Whittle N, Stroobant P, Johnsson A, Wasteson A, Westermark B, Heldin C H, Huang J S, Deuel T F: Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sarcoma virus.Nature 304, 35 (1983).

  41. 41.

    Doolittle R F, Hunkapiller M W, Hood L E, Devare S G, Robbins K C, Aaronson S A, Antoniades H N: Simian sarcoma virus one gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor.Science 221, 275 (1983).

  42. 42.

    Downward J, Yarden Y, Mayers E, Scrace G, Totty N, Stockwell P, Ulrich A, Schlessinger J, Waterfield M D: Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences.Nature 307, 521 (1984).

  43. 43.

    Sherr C J, Rettenmier C W, Sacca R, Roussel M F, Look A T, Stanley E R: The c-fims proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor CSF-1.Cell 41, 665 (1985).

  44. 44.

    Lotem J, Sachs L:In vivo induction of normal differentiation in myeloid leukemic cells.Proc Natl Acad Sci, USA 75, 3781 (1978).

  45. 45.

    Lotem J, Sachs L:In vivo inhibition of the development of myeloid leukemia by injection of macrophage and granulocyte inducing protein.Int J Cancer 28, 375 (1981).

  46. 46.

    Lotem J, Sachs L: Control ofin vivo differentiation of myeloid leukemic cells. IV. Inhibition of leukemia development by myeloid differentiation-inducing protein.Int J Cancer 33, 147 (1984).

  47. 47.

    Lotem J, Sachs L: Control ofin vivo differentiation of myeloid leukemic cells. V. Regulation by response to antigen.Leukemia Res 9, 249 (1985).

  48. 48.

    Gootwine E, Webb C G, Sachs L: Participation of myeloid leukemic cells injected into embryos in hematopoietic differentiation in adult mice.Nature 299, 63 (1982).

  49. 49.

    Webb C G, Gootwine E, Sachs L: Developmental potential of myeloid leukemia cells injected into mid-gestation embryos.Devel Biol 101, 221 (1984).

  50. 50.

    Lotem J, Sachs L: Different blocks in the differentiation of myeloid leukemic cells.Proc Natl Acad Sci, USA 71, 3507 (1974).

  51. 51.

    Friend C: The phenomenon of differentiation in murine erythroleukemic cells.Harvey Lectures, Vol. 72, pp. 253–281. New York, Academic Press (1978).

  52. 52.

    Marks P, Rifkind R A: Erythroleukemia differentiation.Ann Rev Biochem 47, 419 (1978).

  53. 53.

    Symonds G, Sachs L: Synchrony of gene expression and the differentiation of myeloid leukemic cells: reversion from constitutive to inducible protein synthesis.EMBO J 2, 663 (1983).

  54. 54.

    Stewart T A, Mintz B: Successive generations of mice produced from an established culture line of euploid teratocarcinoma cells.Proc Natl Acad Sci, USA 78, 6314 (1981).

  55. 55.

    Rabinowitz Z, Sachs L: Reversion of properties in cells transformed by polyoma virus.Nature 220, 1203 (1968).

  56. 56.

    Rabinowitz Z, Sachs L: Control of the reversion of properties in transformed cells.Nature 225, 136 (1970).

  57. 57.

    Berwald Y, Sachs L:In vitro cell transformation with chemical carcinogens.Nature 200, 1182 (1963).

  58. 58.

    Berwald Y, Sachs L:In vitro transformation of normal cells to tumor cells by carcinogenic hydrocarbons.J Natl Cancer Inst 35, 641 (1965).

  59. 59.

    Borek C, Sachs L:In vitro cell transformation by X-irradiation.Nature 210, 276 (1966).

  60. 60.

    Borek C, Sachs L: Cell susceptibility to transformation by X-irradiation and fixation of the transformed state.Proc Natl Acad Sci, USA 57, 1522 (1967).

  61. 61.

    Rabinowitz Z, Sachs L: The formation of variants with a reversion of properties of transformed cells. V. Reversion to a limited life span.Int J Cancer 6, 388 (1970).

  62. 62.

    Hitotsumachi S, Rabinowitz Z, Sachs L: Chromosomal control of reversion in transformed cells.Nature 231, 511 (1971).

  63. 63.

    Yamamoto T, Rabinowitz Z, Sachs L: Identification of the chromosomes that control malignancy.Nature New Biol 243, 247 (1973).

  64. 64.

    Bloch-Shtacher N, Sachs L: Chromosome balance and the control of malignancy.J Cell Physiol 87, 89 (1976).

  65. 65.

    Bloch-Shtacher N, Sachs L: Identification of a chromosome that controls malignancy in Chinese hamster cells.J Cell Physiol 93, 205 (1977).

  66. 66.

    Craig R W, Sager R: Suppression of tumorigenicity in hybrids of normal and oncogene-transformed CHEF cells.Proc Natl Acad Sci, USA 82, 2062 (1985).

  67. 67.

    Noda M, Selinger Z, Scolnick E M, Bassin R H: Flat revertants isolated from Kirsten sarcoma virustransformed cells are resistant to the action of specific oncogenes.Proc Natl Acad Sci, USA 80, 5602 (1983).

  68. 68.

    Murphree A L, Benedict W P: Retinoblastoma: Clues to human oncogenesis.Science 223, 1028 (1984).

  69. 69.

    Ringertz N R, Savage R E:Cell Hybrids. New York, Academic Press (1976).

  70. 70.

    Stanbridge E J, Der C J, Doersen C-J, Nishimi R Y, Peehl D M, Weissman B E, Wilkinson J E: Human cell hybrids: analysis of transformation and tumorigenicity.Science 215, 252 (1982).

  71. 71.

    Evans E P, Burtenshaw M D, Brown B B, Hennion R, Harris H: The analysis of malignancy by cell fusion. X. Re-examination and clarification of the cytogenetic problem.J Cell Sci 56, 113 (1982).

  72. 72.

    Kitchin R M, Gadi I K, Smith B L, Sager R: Genetic analysis of tumorogenesis. X. Chromosome studies of transformed mutants and tumor-derived CHEF/18 cells.Somat Cell Genet 8, 677 (1982).

  73. 73.

    Benedict W F, Weissman B E, Mark C, Stanbridge E J: Tumorigenicity of human HT1080 fibrosarcoma × normal fibroblast hybrids: Chromosome dosage dependency.Cancer Res 44, 3471 (1984).

  74. 74.

    Azumi J, Sachs L: Chromosome mapping of the genes that control differentiation and malignancy in myeloid leukemic cells.Proc Natl Acad Sci, USA 74, 253 (1977).

  75. 75.

    Frankel A E, Haapala D K, Newbouer R L, Fischinger P J: Elimination of the sarcoma genome from murine sarcoma virus transformed cat cells.Science 191, 1264 (1976).

  76. 76.

    Fibach E, Landau T, Sachs L: Normal differentiation of myeloid leukemic cells induced by a differentiation-inducing protein.Nature New Biol 237, 276 (1972).

  77. 77.

    Lotem J, Sachs L: Potential pre-screening for therapeutic agents that induce differentiation in human myeloid leukemic cells.Int J Cancer 25, 561 (1980).

  78. 78.

    Lotem J, Berrebi A, Sachs L: Screening for induction of differentiation and toxicity to blast cells by chemotherapeutic compounds in human myeloid leukemia.Leukemia Res 9, 249 (1985).

  79. 79.

    Castaigne S, Daniel M T, Tilly H, Herait P, Degos L: Does treatment with ara-C in low dosage cause differentiation of myeloid leukemic cells?Blood 62, 85 (1983).

  80. 80.

    Wischz J S, Griffin J D, Kuffe D W: Response of preleukemic syndromes to continuous infusion of low-dose cytarabine.New Engl J Med 309, 1599 (1983).

  81. 81.

    Manoharan A: Low dose cytarabine therapy in hypoplastic acute leukemia.New Engl J Med 309, 1652 (1983).

  82. 82.

    Mufti G J, Oscier D G, Hamblin T J, Bell A J: Low doses of cytarabine in the treatment of myelodysplastic syndrome and acutue myeloid leukemia.New Engl J Med 309, 1653 (1983).

  83. 83.

    Michalewicz R, Lotem J, Sachs L: Cell differentiation and therapeutic effect of low doses of cytosine arabinoside in human myeloid leukemia.Leukemia Res 8, 783 (1984).

  84. 84.

    Ishikura H, Sawada H, Okazaki T, Mochizuki T, Izumi Y, Yamagishi M, Uchino H: The effect of low dose Ara-C in acute non-lymphoblastic leukaemias and atypical leukaemia.Br J Haemat 58, 9 (1984).

  85. 85.

    Tilly H, Castaigne S, Bordessoule D, Sigaux F, Daniel M-T, Monconduit M, Degos L: Low-dose cytosine arabinoside treatment for acute nonlymphocytic leukemia in elderly patients.Cancer 55, 1633 (1985).

  86. 86.

    Jensen M K, Ahlbom G: Low dose cytosine arabinoside in the treatment of acute non-lymphocytic leukaemia.Scand J Haemat 34, 261 (1985).

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Sachs, L. Hematopoietic growth and differentiation factors and the reversibility of malignancy: Cell differentiation and by-passing of genetic defects in leukemia. Med. Oncol. & Tumor Pharmacother. 3, 165–176 (1986). https://doi.org/10.1007/BF02934993

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Key words

  • Hematopoietic growth and differentiation factors
  • Cell differentiation
  • Normal development
  • Leukemia
  • Reversibility of malignancy
  • By-passing genetic defects