Britishjournal ofHuernatology, 1978,40, 509-517.

Annotation THE DIFFERENTIATION O F MYELOID LEUKAEMIA CELLS: NEW POSSIBILITIES FOR THERAPY The development of experimental systems for the culture and cloning of normal haematopoietic cells (Ginsburg & Sachs, 1963, 1965; Sachs, 1964, 1974a, b; Pluznik & Sachs, 1965, 1966; Ichikawa et al, 1966; Bradley & Metcalf, 1966; Paran et al, 1970),has made it possible to study the controls that regulate haematopoietic cell differentiation and the blocks that can occur in luekaemia. All the main types of mammalian haematopoietic cells can be cloned in culture (Ginsburg & Sachs, 1963; Pluznik & Sachs, 1965; Ichikawa et al, 1966; Bradley & Metcalf, 1966; Stephenson et al, 1971; Metcalfet al, 1975;Gerassi & Sachs, 1976;Fibach et al, 1976; Sredni et al, 1976). Normal myeloid precursors can be induced to differentiate to mature macrophages and granulocytes by the protein inducer (Pluznik & Sachs, 1965,1966; Ichikawa et al, 1976)that we now call MGI (macrophage and granulocyte inducer) (Landau & Sachs, 1971; Sachs, 1974a, b). This inducer is secreted by various types of cells including fibroblasts and macrophages and can also be found in human serum (Mintz & Sachs, 1973b). Unless otherwise stated, all the experiments described in this paper have been carried out with cells from mice. MGI, which has also been referred to as mashran gm (Ichikawa et al, 1967), colony stimulating factor (Metcalf, 1969) or colony stimulating activity (Austin et al, 1971), is specific for the induction of macrophages and granulocytes. Purified MGI from fibroblasts has a molecular weight of about 68 ooo (Landau & Sachs, 1971; Guez & Sachs, 1973; Stanley & Heard, 1977), purified MGI from lungs a molecular weight of about 23 ooo (Burgess et al, 1977) and the lower molecular weight may be derived from the higher molecular weight MGI. Purified MGI can induce the formation of macrophages and granulocytes. There may, however, also be molecular forms that induce only macrophages or granulocytes and different co-factors (Landau & Sachs, 1971; Sachs, 1974b) that can influence the differentiation to one or the other cell type. Incubation of the precursor cells with MGI for different periods of time has indicated that MGI has to be present until the process of differentiation is completed (Pluznik & Sachs, 1966; Paran & Sachs, 1968). Normal myeloid precursors require MGI for cell viability, growth and differentiation. It remains to be determined whether these properties can all be induced by MGI molecules with the same chemical composition. Normal Differentiation of Myeloid Leukaemic Cells Using leukaemic cells from different myeloid leukaemias we have shown that there is one type of myeloid leukaemic cell in humans (Paran et al, 1970) and mice (Sachs, 1974a, b, 1977) that can be induced to differentiate normally both in vitro and in vivo, and that this differentiation can be regulated by cells involved in the immune response (Lotem & Sachs, 1978). The experiments with mice have shown that induction of differentiation to mature macrophages Correspondence: Professor Leo Sachs, Department of Genetics, Weizmann Institute of Science, Rehovot, Israel. 0007- 1048178/ I 200-0 509$0z .oo

0I 978 Blackwell Scientific Publications

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and granulocytes can be obtained with purified MGI (Fibach et al, 1972) (Fig I). This type of leukaemia has been cloned in culture (Ichikawa, 1969; Fibach et al, 1972, 1973) and will be referred to as MGI+D+(D+for differentiation to mature cells) (Fibach et al, 1973).Like normal macrophages and granulocytes, the mature cells induced from these leukaemic cells are no longer malignant in viuo and no longer multiply in vitro (Fibach & Sachs, 197s). Unlike mouse erythroleukaemic cells (Friend et al, 1971) that have lost the ability (Kluge et al, 1974) to respond to the normal erythroid inducing protein erythropoietin (Krantz &Jacobson, 1970), these MGI+D+ myeloid leukaemic cells can still respond to the normal myeloid inducing protein MGI. Isolation of the myeloid precursor cells from normal bone marrow (Lotem & Sachs, 1977a), has made it possible to compare the sequence of differentiation in normal myeloid and MGI+D+leukaemic cells. The results have shown that both the normal and these leukaemic cells were induced by MGI not only to produce the same mature cells, macrophages and granulocytes, but that the process of differentiation occurred in the same sequence. The sequence of differentiation in both cases was the induction of C3 and Fc rosettes (Lotem & Sachs, 1974),C3 and Fc immune phagocytosis (Lotem & Sachs, 1977b), synthesis and secretion of lysozyme (Krystosek & Sachs, 1976) and the formation of mature macrophages and granulocytes (Paran et al, 1970; Fibach et al, 1972, 1973; Lotem & Sachs,.1977b). T h e Development of Myeloid Leukaemia Although both the normal and MGI+D+ leukaemic cells can be induced to differentiate normally by MGI, the normal cells differ from those that are leukaemic in that the leukaemic cells are viable and can grow in the absence of MGI whereas the normal cells require MGI for cell viability and growth (Fibach & Sachs, 1976).These leukaemic cells are therefore malignant not because they can not be induced to differentiate by the normal inducing protein, but because they no longer require this protein for viability and growth. The absence of an adequate supply of MGI in vivo would thus limit the growth of the normal cells, but would not effect the growth of the leukaemic cells. A change in the cells resulting in a partial or complete loss of the requirement of this protein for viability and growth may thus be the cause of myeloid leukaemia. The MGI+D+ leukaemic cells studied did not have a normal dipoid karyotype and the change in the requirement for MGI for cell viability and growth was associated with a chromosome abnormality (Hayashi et al, 1974; Azumi & Sachs, 1977). This suggests that the origin of leukaemia due to a loss in the requirement for MGI for viability and growth is genetic and due to a chromosomal change. Studies with different types of myeloid leukaemic cells have indicated that once the change has occurred which allows the leukaemic cells to grow in the absence of MGI, this can then be followed by other genetic changes that produce blocks in the induction of differentiation by MGI. The isolation and study of such mutants (Fibach et al, 1973; Lotem 81 Sachs, 1974,197~a, 1976, I977b; Krystosek & Sachs, 1976)has shown that there can be blocks at different stages of differentiation and that there are separate controls for the induction of Fc rosettes, C3 rosettes, Fc immune phagocytosis, C3 immune phagocytosis, synthesis and secretion of lysozyme, formation of mature macrophages and the formation of mature granulocytes (Lotem & Sachs, 1977b). Mutants have also been isolated which differ in the time of induction and in the

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FIG I. Differentiation of MGI+D cells to mature macrophages and granulocytes by MGI. Undifferentiated blast cell (A), stages in the differentation to mature graiiulocy (B-D), macrophage (E) and a group of granulocytes in different stages of differentiation (F). +

(Facing p . 5 I 0)

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sequence of differentiation. In one such mutant, MGI induced the synthesis and secretion of lysozyme without going through the stage of Fc and C3 immune phagocytosis (Lotem & Sachs, 1977b).The isolation of other mutants should make it possible to further define not only the degree of independence of the control for each marker, but also to determine to what extent other stages in the sequence can be omitted or sequences can be reversed and the cells still proceed to the next stage. It will also be interesting to find mutants that still require MGI for viability and growth but are blocked in differentiation, and to determine whether such cells are malignant. Karyotype analysis of cells with different degrees of competence for the induction of differentiation by MGI has shown that genes that control cell competence are located on mouse chromosomes 2 and 12, and that inducibility by MGI is controlled by the balance between these genes (Azumi & Sachs, 1977). It has been suggested that these chromosomes also carry genes that control the malignancy of these cells (Azumi & Sachs, 1977).Karyotype analysis in human myeloid cells have also shown specific chromosome changes in human myeloid leukaemia (Rowley, 1977). It will be of interest to determine the behaviour of leukaemic cells with different degrees of competence for induction of differentiation after inoculation into blastocysts, as has been done with teratocarcinoma cells (Mintz & Illmensee, 1975) and after culture on fat cells from the bone marrow (Dexter et al, 1977).

Induction of Some Stages of Differentiation by Treatment with Different Compounds Studies with various compounds, including those used in cancer therapy, have shown that some of the stages of differentiation can be induced in appropriate clones of myeloid leukaemic cells by certain steroids such as dexamethasone, prednisolone and oestradiol (Lotem & Sachs, 1974, 1975a), presumably surface acting agents such as the lectins Con A, phytohaemmaglutinin, pokeweed mitogen (Lotem & Sachs, 1978), lipopolysaccharide, lipid A (Weiss & Sachs, 1978) and dimethylsulphoxide (DMSO) (Krystosek & Sachs, 1976; Maeda & Sachs, 1978), actinomycin D and other compounds that can interact with DNA such as cytosine arabinoside, mitomycin C, 5-bromodeoxyuridine (Lotem & Sachs, 1974, 1975b) nitrosoguanidine and X-irradiation (A. Falk and L. Sachs, unpublished), some carcinogenic hydrocarbons ( Z . Schwarzbard and L. Sachs, unpublished). Compounds that can induce some normal cell markers in an appropriate clone of MGI+D+leukaemic cells are shown in Table I. Not all the compounds induced the same markers or induced changes in the same clones. MGI was the only compound that induced all the changes to mature macrophages and granulocytes. An example of the dissection of the controls for induction by a steroid inducer (SI) such as dexamethasone and MGI is shown in Fig 2 . The data show that MGI and SI do not induce the same markers even in clones (SI+MGI+)that respond to both compounds and that it is possible to isolate mutants that are SI+MG-, SI-MG- (Lotem & Sachs, 1976) or SI-MGI+ (L. Cohen and L. Sachs, unpublished). The lack of response to dexamethasone in the SI clones was not due to any detectable defect in the number, nuclear transport, or association with DNA containing structures of the steroid receptors (Krystosek & Sachs, 1977).The results indicate that there are different cellular sites for MGI and a steroid inducer such as dexamethasone. DMSO induced C3 but not Fc rosettes, and macrophages but not granulocytes, in a MGI+SI+DMSO+clone. W e have also isolated MGI+SI+DMSO- clones (Krystosek & Sachs, 1976; Maeda & Sachs, 1978), so that there appear to be different cellular sites for DMSO, SI and MGI. Mouse

FIG 2. Inducibility for differentiation-associated markers in different clones of myeloid leukaemic cells by the steroid inducer (SI) dexamethasone and the normal regulatory protein MGI. Clones that could be induced to differentiate to mature cells are referred to as D+.

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TABLE I. Inducers and non-inducers for normal cell markers in MGI+D+ niyeloid leukaemic cells. The different inducers were not all active on the same clone and did not all induce the same markers. ~

T y p e of compound

Inducers

Peptide hormones

MGI

Steroids

Dexamethasone, prednisolone, hydrocortisone, oestradiol

Lectins

Concanavalin A, phytohaemmaglutinin, pokeweed mitogen Benzo(a)pyrene, dimethylbenz(a)anthracene

Polycyclic hydrocarbons

Other compounds

Lipopoly saccharide, lipid A, mitomycin C, dimethylsulphoxide cytosine arabinoside, hydroxyurea, thymidine, 5-iododeoxyuridine, 5-bromodeoxyuridine, 5-fluorodeoxyuridine, nitrosoguanidine, actinomycin D, adriamycin, daunomycin, X-irradiation, I 2-0-tetradecanoylphorbol-x 3acetate

~

Non-inducers

Erythropoietin, nerve growth factor, insulin, ubiquitin, thymopoietin, interferon Progesterone, testosterone, epitestosterone, androstenedione. cortisone

Benz(a)anthracene, dibenz(a,c)anthracene, dibenz(a,h)anthracene, phenanthrene Colchicine, vinblastine, Na butyrate, Cycloheximide, db cyclic AMP, d b cyclic GMP, cordycepin, deoxyglucose, ouabain, ionophore 23 187

erythroleukaemia cells can be induced to partially differentiate by DMSO (Friend et al, 1971) and some other compounds and there also appear to be different cellular sites for different compounds (Nude1et al, 1977; Ohta et al, 1976).However, in contrast to these erythroleukaemic cells that can be induced to partially differentiate by a compound such as DMSO but which have lost the ability to respond to erythropoietin, the MGI+DMSO+myeloid leukaemic cells can still respond to MGI. Among the compounds that induced differentiation to macrophages in some MGI+D+ clones were lipopolysaccharides (LPS)from different bacteria. LPS induced a high frequency of Fc and C3 rosettes, lysozyme and macrophages in certain clones of MGI+D+cells, but not in MGI+D- clones. Similar results were obtained with lipid A, so that the active part of the LPS molecule appears to be lipid A. The results have also shown that treatment of the responding MGI+D+ clones with LPS or lipid A induced an activity in the conditioned medium that behaved like MGI (Weiss & Sachs, 1978).This shows that appropriate clones ofleukaemic cells can be induced to produce their own normal differentiation inducer. Studies on the time of induction of detectable MGI after treatment of MGI+D+cells with LPS have indicated that induction of MGI was detected before the induction of rosettes or lysozyme. These results

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indicate that the lipid A portion of LPS indirectly induces differentiation of MGI+D+myeloid leukaemic cells by inducing in these cells production of the differentiation-inducing protein MGI (Weiss & Sachs, 1978). It will be of intsrest to determine which of the other compounds that can induce differentiation-associated properties in MGI+D+leukaemic cells act directly and which, like lipid A, may induce differentiation indirectly by inducing the production of MGI. The induction of regulatory proteins that can induce specific cell differentiation may be a more general mechanism for the induction of differentiation by various compounds in different cell types.

New Possibilities for Therapy Our results suggest some novel possibilities for leukaemia treatment (Paran et al, 1970; Fibach et al, 1972; Sachs, 1974a, 1976), that may also be applicable to other types of tumours. The finding of MGI+D+myeloid leukaemic cells that can be induced to differentiate normally by MGI, suggests MGI injection, grafting of MGI producing cells, or stimulation of the in vivo production of MGI to induce the normal differentiation of these leukaemic cells. This would be a form of tumour therapy that is not based on the search for cytotoxic agents which selectively kill tumour cells. The membrane differences between cells which differ in their competence to be induced to differentiate by MGI (Sachs, 1974a; Lotem et al, 1976; Liebermann & Sachs, 1977; Simantov & Sachs, 1978), may be useful predictive markers of response to MGI in vivo. MGI+D+leukaemic cells can be induced by MGI to again require this protein for cell viability and growth. This suggests that induction of differentiation of the leukaemic cells to this stage, followed by the withdrawal of MGI, may also result in the loss of viability and growth of the induced MGI+D+leukaemic cells in vivo. The induction of normal macrophage and granulocyte differentiation by MGI also suggests that injection or stimulation of in vivo production of MGI, may be of value for rapid recovery of the normal macrophage and granulocyte population after cytotoxic therapy. It may also be useful for treatment of non-malignant granulocyte diseases (Paran et al, 1970; Barak ef al, 1971; Mintz & Sachs, 1973a). Our results also help to explain the response of some, but not all, patients to chemical and irradiation cytotoxic therapy. Chemicals and irradiation used in therapy can induce some stages of differentiation in clones of myeloid leukaemic cells with the appropriate genotype, and clonal differences in inducibility for normal differentiation-associated properties are not necessarily associated with differences in the response of these clones to the cytotoxic effect of these compounds. Cells with induced Fc and C3 receptors, phagocytosis, and other macrophage-like properties, can be expected to behave differently in the body in their response to a variety of factors including antibodies, than cells without these properties. The in vivo growth of leukaemic cells with the appropriate genotype may thus be controlled by the therapeutic agents used not only because of their cytotoxic effect, but because they induce these differentiation-associated properties. Differences in competence to be induced by these agents may thus explain differences in response to therapy in different individuals. The possible induction of MGI by these compounds may also play a role in the therapeutic effects obtained in vivo. The results obtained with these myeloid leukaemic cells therefore suggest possible forms of therapy based on the use of a normal regulatory protein such as MGI to induce normal differentiation in malignant cells and a more rapid recovery of the normal cell population after

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the present forms of therapy. They also suggest the use of other compounds that can induce the normal regulatory protein, or can effect mutant malignant cells at differentiation sites no longer susceptible to the normal regulator. L. SACHS Department of Genetics, Weizmann Institute of Science, Reho vot, Israel REFERENCES AUSTIN, P.E., MCCULLOCH, E.A. & TILL, J.E. (1971)

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81 OSTERTAG, W. (1974) Globin synthesis in Frienderythroleukemia mouse cells in protein- and lipidfree medium. Experimental Cell Research, 88, 2 $7-262. KRYSTOSEK, A. & SACHS,L. (1976) Control of lysozyme induction in the differentiation of myeloid leukemic cells. Cell, 9, 675684. KRYSTOSEK, A. & SACHS, L. (1977) Steroid hormone receptors and the differentiation of myeloid leukemic cells.Journal ofcellular Physiology, 92,345-352. LANDAU, T. 81 SACHS,L. (1971) Characterization of the inducer required for the development of macrophage and granulocyte colonies. Proceedings of the National Academy of Sciences of the United States of America, 68, 25qo-zj44. LIEBERMANN, D. & SACHS,L. (1977) Type C RNA virus production and cell competence for normal differentiation in myeloid leukemic cells. Nature, 2 6 9 9 173-175. LOTEM, J. & SACHS, L. (1974) Different blocks in the differentiation of myeloid leukemic cells. Proceedings ofthe National Academy of Sciences of the United States of America, 71, ~ $ o ’ / - ~ s I I . J. & SACHS,L. (197~a)Induction of’specific LOTEM, changes in the surface membrane of myeloid leukemic cells by steroid hormones. International Journal ofcancer, 15. 73 1-740. DTEM,J. & SACHS,L. (197~b)Control of normal differentiation of myeloid leukemic cells. VI. Inhibition of cell multiplication and the formation of macrophages. Journal of Cellular Physiology, 85, 587394. DTEM,J. & SACHS,L. (1976) Control of Fc and C3 receptors on myeloid leukemic cells. Journal of Immunology, 117,580-586. LOTEM,J. & SACHS,L. (1977a) Control of normal differentiation of myeloid leukemic cells. XII. Isolation of normal myeloid colony-forming cells from bone marrow and the sequence of differentiation to mature granulocytes in normal and D+ myeloid leukemic cells. Journal of Cellular Physiology, 92, 97- 108. LOTEM, J. & SACHS, L. (1977b) Genetic dissection of the control of normal differentiation in myeloid leukemic cells. Proceedings ofthe National Academy of Sciences of the United States of America, 74. 5 5 54-5 5 5 8. LOTEM,J. & SACHS,L. (1978) In uivo induction of normal differentiation in myeloid leukemic cells. Proceedings of the National Academy of Sciences of the United States of America, (in press). J., VLODAVSKY, I. & SACHS,L. (1976) RegulaLOTEM, tion of cap formation by concanavalin A and the differentiation of myeloid leukemic cells: Relationship to free and anchored surface receptors. Experimental Cell Research, 101, 323-330. MAEDA,S. & SACHS,L. (1978) Control of normal

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Annotation ROWLEY, J.D. (1977) Mapping of human chromosomal regions related to neoplasia: Evidence from chromosomes I and 17. Proceedings ofthe National Academy of Sciences of the United States of America, 749 5729-5733. SACHS, L. (1964) The analysis of regulatory mechanisms in cell differentiation. N e w Perspectives in Biology, pp. 246-260. Elsevier, Amsterdam. SACHS, L. (1974a) Regulation of membrane changes, differentiation and malignancy in carcinogenesis. Harvey Lectures, 68, 1-35. Academic Press, New York. SACHS, L. (1974b) Control of growth and differentiation in normal hematopoietic and leukemic cells. Control ofProlifration in Animal Cells, pp. 915-925. Cold Spring Harbor Lab., New York. SACHS, L. (1976) Control of normal cell differentiation in leukemic cells. Comparative Leukemia Research, pp. 6-9. Karger, Basel. SACHS, L. (1978) Control ofnormal cell differentiation in leukemic white blood cells. In: M.D. Anderson Symposium on Cell Dtfferentiation and Neoplaria, pp. 223-239. Raven Press, New York. SIMANTOV, R. & SACHS, L. (1978) Differential desensi-

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The differentiation of myeloid leukaemia cells: new possibilities for therapy.

Britishjournal ofHuernatology, 1978,40, 509-517. Annotation THE DIFFERENTIATION O F MYELOID LEUKAEMIA CELLS: NEW POSSIBILITIES FOR THERAPY The develo...
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