Autocrine Growth Factors and Leukaemic Haemopoiesis

N. H. Russell S EMMA R Y. Studies on the structure of haemopoiesis in acute myeloblastic leukaemia (AML) has shown the presence of a small population of malignant cells with extensive proliferative and selfrenewal properties which are features of stem cells. The requirements of these cells for proliferation have been studied both in clonogenic assays in semi-solid media and in liquid suspension culture. These have demonstrated that AML clonogenic cells from the majority of patients, can be stimulated to proliferate by colony-stimulating factors (GM-CSF, GCSF and IL-3) as well as other cytokines including interleukin-1 and interleukin-6, all of which are known to stimulate normal haemopoietic progenitors. Unlike normal haemopoietic cells, leukaemic blasts from many patients with AML express transcripts for haemopoietic growth factors including GM-CSF, GCSF and IL-1 but not IL-3, and secrete growth factor protein. When leukaemic cells are cultured at sufficiently high density to permit cell-cell interactions, autonomous growth of clonogenic cells can be seen. Autonomous growth is related to the autocrine secretion of haemopoietic growth factors including GM-CSF, G-CSF and IL-6. The degree of autonomous colony growth is variable but approximately 70% of AML samples exhibit either partial or totally autonomous growth; the remaining cells being absolutely dependent on exogenous CSF or fail to grow in the culture systems employed. Similar patterns of growth have been found in murine haemopoietic cells lines which have been transformed as the result of the retroviral insertion of genes for GM-CSF or IL-3. AML blasts from many patients also secrete IL-1 which has been shown to regulate the autocrine production of GM-CSF, G-CSF and IL-6 by leukaemic cells and may also stimulate paracrine CSF secretion of these cytokines by bone marrow stromal cells. Thus Interleukin-1 appears to play a major hierarchic role in the autocrine circuits operating in AML blasts which regulate leukaemic cell proliferation in vitro and may be involved in the initiation or progression of the disease in vivo.

Acute myeloblastic leukaemia (AML) is a clonal haematopoietic disorder characterised by the rapid proliferation of malignant blast cells and the suppression of normal haemopoiesis. The structure of haemopoiesis in AML has some features in common with that of the normal haemopoietic system in that there is a hierarchical organisation of leukaemic cells with a small population of stem cells maintaining the N. H. Russell MD, MRCP (UK), MRCPath, in Haematology, Department of Haematology, Nottingham NG5 IPB, UK. Correspondence to: N. H. Russell. Blood Reviews (1992) 6, 149-156 IC’ 1992 Longman Group UK Ltd

Senior Lecturer City Hospital,

leukaemic clone. As in normal haemopoiesis, the proliferation of leukaemic cells is dependent upon the stimulation provided by a complex network of haemopoietic growth factors (colony stimulating factors). Unlike normal haemopoiesis, differentiation of leukaemic blasts is totally or partially blocked leading to the accumulation of blast cells. Also there is a considerable amount of evidence that some AML blasts produce autocrine growth factors which have an important role in the proliferation of leukaemic cells in vitro and may also have a role in the occurrence and progression of the leukaemic clone in vivo.

150

AUTOCTINE GROWTH FACTORS AND LEUKAEMIC

Structure of Haemopoiesis Leukaemia

in Acute Myeloblastic

Hierarchy of Leukaemic Haemopoiesis Normal peripheral blood granulocytes, monocytes, erythrocytes and platelets are derived from small numbers of bone marrow progenitor cells that have extensive proliferative capacity.’ The identification of normal progenitor cells has depended upon their proliferation to form identifiable colonies in semisolid tissue culture medium in the presence of specific growth factors. The application of similar techniques to the blast cells of AML has lead to a model of leukaemic haemopoiesis which proposes the existence of a small population of leukaemic stem cells which have extensive proliferative capacity.2 The colonies grown in leukaemic blast cell assays consist of cells with the morphologic phenotypic and karyotypic characteristics of AML blasts,23 indicating that leukaemic progenitors in vitro also fail to undergo the normal differentiation programmes that is characteristic of AML cells in vivo. A stimulator of colony growth is provided in these assays, in early studies this was usually medium conditioned by normal leucocytes in the presence phytahaemagglutinin (PHA),3 which is known to a number of haematopoietic growth factors. Even in these early studies it was identified that spontaneous or autonomous blast cell colony growth was seen in some cases, in the absence of exogenous growth factors3 Studies involving the replating of cells from single or pooled colonies identified that a small population of colony forming cells were capable of giving rise to daughter cells with AML colony forming capacity, i.e. that these cells exhibited the property of self-renewal which is a feature of stem cell populations4 As in normal haemopoiesis, AML cells can be cultured long term in suspension culture for several weeks.’ However unlike long term bone marrow cultures derived from normal bone marrow, long term cultures of AML cells proliferate in the absence of a defined stromal layer, although it was found to be imperative to maintain the leukaemic cells at a high cell density.5 These studies on AML blasts have lead to a concept of a hierarchical model of leukaemic haemopoiesis consisting of heterogeneous population of cells with a small number of self-renewing leukaemic stem cells with extensive proliferative capacity and a population of proliferatively inert blast cells which make up the vast majority of identifiable leukaemic cells.2v3*4 Further support for this model came from studies of the surface phenotype AML cells, which demonstrated that the phenotype of the clonogenic cells was not infrequently different to that expressed by the majority population of AML blasts.6*7 Thus antigens appearing ‘late’ in normal haemopoiesis although expressed on the majority of AML cells were lacking on clonogenic cells7 thus implying that AML progenitors are capable of limited differentiation which is linked to a reduction in proliferative potential. The

HAEMOPOIESIS

immunophenotype of AML progenitors was found to be heterogeneous and have features in common with either committed myeloid progenitor cells (CFUGM) or multipotent progenitors (CFU-GEMM).6g7 Similarly the CD34 antigen which is expressed on normal myeloid, erythroid and megakaryocytic* progenitors is also frequently expressed on AML clonogenie cells. 9~10Overall this data can be interpreted as indicating that the progenitor cells in AML express the phenotype of the normal hemopoietic precursor which in an individual case reflects the cellular origin of the leukaemia. Autonomous Growth of AML Clonogenic Cells Over the past few years a considerable amount of evidence has been produced that under certain culture conditions AML blasts can proliferate autonomously. 11-14 The prerequisites for autonomous growth include that the leukaemic cells should be cultured at a sufficiently high cell density to allow for cell-cell interactions to take place.12*13*‘5This can be achieved in either suspension or methylcellulose culture and by measuring either spontaneous DNA synthesis, or by enumerating colonies, in the presence or absence of a source of haemopoietic growth factors. The first observations of the autonomous proliferation of clonogenic AML blasts were made by Young and Griffinl’ who reported two cases of autonomous leukaemic colony growth in agar culture. A more comprehensive analysis of AML blast cell proliferation involving a study of 25 AML samples lead us to propose a classification of AML growth properties based upon the presence or absence of autonomous growth characteristics in methyl cellulose culture.i2 Four major groups of AML blasts were identified. Group 1 blasts failed to grow in the culture system either in the presence or absence of exogenous growth factor provided by conditioned medium from the 5637-bladder carcinoma cell line (5637-CM). Group 2 blasts formed colonies in methyl cellulose but were totally dependent upon the presence of 5637-CM. Group 3 blasts exhibited a variable degree of autonomous growth but could be further stimulated by growth factors present in 5637-CM (See Fig. 1). Group 4 blasts exhibited totally autonomous growth. These findings were corroborated by measuring DNA synthesis of blasts grown in suspension culture, in these experiments it was observed that the proliferation of group 3 blasts was particularly dependent upon cell density. At low cell density, cells were relatively dependent upon exogenous CSF, but progressive autonomy was seen with increasing cell density. l2 In this series 70% of AML blasts exhibited some degree of autonomous growth (group 3 or group 4 growth characteristics). Other investigators have also found a high incidence of density-dependent autonomous growth of clonogenic AML blasts.‘3-‘5 As shall be seen in the following sections, patterns

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Fig. 1 Blast cell colonies from a patient with AML exhibiting group 3 partially autonomous growth characteristics. Above shows colonies grown in absence of added growth factors, and below shows more numerous and larger colonies grown in presence of 5637-CM.

of growth very similar to that described here in primary cultures of AML blasts, have been reported in cell lines manipulated in various ways to induce the expression of haemopoietic growth factors. Huemopoietic Growth Factors in AML Blast Proliferation The fundamental role played by specific growth factors in controlling the proliferation of normal haemopoietic cells has been well established.’ Clonogenie assays with AML cells cultured at low cell densities have been demonstrated that leukaemic blast progenitors proliferate in culture in the presence of recombinant colony-stimulating factors (CSF) including granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF) and interleukin-3 (ILand IL-3 have been found 3). 14.16*L7,18,19GM-CSF to have an equivalent activity in stimulating progenitor cell proliferation which is usually greater than that seen with G-CSF.” The response of AML blasts to these growth factors shows marked patient to patient variation in responsiveness”v2’ which is in keeping with the heterogeneity of AML clones in immunophenotypic studies. This heterogeneity has not been shown to correlate with the morphological (FAB) subtype of the disease. The effect of any single growth factor has been found to be frequently sub-

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optimal and combinations of factors such as G-CSF with GM-CSF have been seen to be synergistic17v2’ in stimulating proliferation. The responsiveness of AML cells to IL-3 has been shown to be similar to the response to GM-CSF and GM-CSF combined with IL-3 did not synergise, suggesting that two cytokines act upon the same leukaemic precursor population whereas G-CSF acts upon different subsets present within the same clone.14.r7 M-CSF has been found to be an infrequent inducer of AML cell growth.14 Other cytokines have been implicated in the regulation of early events in normal haemopoiesis, these include IL-I (21) and IL-6.22 When incubated with AML blasts at low cell concentration, IL- I was found to synergise with GM-CSF and G-CSF in stimulating the proliferation of clonogenic cells.23 IL-l has complex effects on AML cells including a pivotal role in autocrine growth factor production (vide infra), however it would appear from these careful experiments that IL-l does have direct effects on AML blasts, sensitising them to the effects of GM-CSF and G-CSF.23 Similarly IL-6, which has been shown to enhance IL-3 dependent proliferation of normal multipotent stem cells22 also synergises with GMCSF in stimulating AML blast cell growth.” Tumour necrosis factor (TNF-a) has a complex bidirectional effect on AML blast cell proliferation. When cultured at low density, TNFcl synergises with GM-CSF and IL-3 to stimulate proliferation2’ an effect possibly mediated by an up-regulation of shared surface receptors for these cytokines.26.27 In contrast, TNFcl inhibits the stimulatory effects of G-CSF on AML blasts25.28 by down-regulating G-CSF receptors.29 These effects on AML blast cell progenitors parallel the effects of TNFa on normal haemopoietic progenitors. 3o These analyses of the effects of haemopoietic growth factors does not reveal any findings which suggest a differential effect on leukaemic compared to normal progenitors. In contrast the data suggests that the leukaemic progenitors have similar responses to growth factors as their counterparts in normal haemopoiesis.

Evidence for Autocrine Mechanisms Haemopoiesis

in Leukaemic

The potential significance of autocrine growth factor production by neoplastic cells has been extensively reviewed.31 Cancer cells able to produce and respond to their own growth factors could become independent of the growth regulatory constraints placed upon normal cells thus providing a major growth advantage to the malignant clone. Two patterns of autocrine growth of tumour cells have been described (See Fig. 2). One is the extracellular autocrine loop involving secretion of growth factors by cells which express specific growth factor receptors thus triggering cell proliferation. This dassical autocrine loop can be interrupted by specific

152 AUTOCTINE GROWTH FACTORS AND LEUKAEMIC HAEMOPOIESIS

/

paracrine

Fig. 2 Modes of autocrine growth mechanisms including both intracellular and extracellular growth factors triggering cell division. Both of these mechanisms have been implicated in the transformation of leukaemic cell lines. Alternatively the secretion of growth factors may activate neighbouring leukaemic cells via a paracrine mechanism.

antibodies to the secreted protein. The secreted factor may also act in a paracrine manner on surrounding cells of the tumour which are incapable of synthesising the growth factor. Evidence has been found for a second type of autocrine loop involving non-secreted growth factor32 which activates cells via intracellular compartments as is exemplified by NRK cells transformed by the v-sis oncogene encoding for plateletderived growth factor. 33 The proliferation of cells under the control of intracellular autocrine loops is not density-dependent and cannot be suppressed by antibodies to the relevant growth factor. Examples of both classical and intracellular autocrine loops are found in transformed haemopoietic cell lines and probably also in AML blasts. Evidence from Immortaiised Cell Lines Cells of haematopoietic origin have proven to be of value in studying the link between disturbances in mitogenic signal transduction and leukaemic transformation. Murine FDCP-1 cells are an immortalised cell line, originally derived from long term bone marrow cultures, which have lost their ability to differentiate and depend for their survival on the presence of GM-CSF or IL-3 in the growth medium.34 Although these cells retain a blast like morphology they are not leukaemogenic. However, following insertion of retroviral expression vectors carrying the GM-CSF coding sequence, the virally infected cells synthesised and secreted GM-CSF and

grew autonomously in vitro.35 Importantly the GMCSF transfected cells, unlike the parent factordependent FDCP-1 cells were leukaemogenic when injected into syngeneic mice. Although these cells secreted relatively high levels of GM-CSF, the authors were unable to demonstrate that growth of the cells was dependent on secreted GM-CSF due to a lack of inhibition by GM-CSF antibodies, findings which lead them to speculate the existence of an intracellular autocrine 10op.j~ Insertion of the IL-3 gene into FDCP-1 cells also rendered the cells leukaemogenic, however in this case FDCP- 1-IL-3 cells were dependent upon secreted IL-3, as growth was completely inhibited by IL-3 antisera. 36 However in ex p eriments using an IL-3 gene modified to prevent secretion of IL-3 protein from the endoplasmic reticulum, clones were derived which were autonomous, leukaemogenic and not inhibited by IL-3 antisera.37 These experiments provide direct evidence that IL-3 sequestered within an intracellular compartment can establish a functional autocrine loop. FDCP-1 cells infected with a retrovirus containing the cDNA for polyoma middle T. antigen, generated a number of different cell lines, all of which were leukaemogenic but which exhibited different patterns of growth in vitro. 38 Three major growth patterns were seen (i) absolute dependency on exogenous GMCSF or IL-3 as seen in the parent FDCP-1 cell line; (ii) totally autonomous growth, and (iii) an intermediate pattern of behaviour with dependency on exogenous GM-CSF or IL-3 at low cell density but progressive autonomy as cell density was increased. These results are fascinating in that identical growth patterns have been reported in cultures of human myeloid leukaemias.” Other methods of transformation of FDCP-1 cells have lead to similar findings. FDCP-1 cells transformed either by injection into irradiated syngeneic mice3’ or by exposure to the chemical mutagen, ethyl methane sulphonate 4o also exhibited autocrine production of GM-CSF including further evidence of a role for intracellular autocrine mechanisms. The in vitro growth patterns observed in these cells was identical to that seen in polyoma middle T. antigen transformed cells and indicates that the acquisition of autocrine growth factor production maybe an important mechanism for the final leukaemic transformation of these cell lines. However FDCP-1 is highly abnormal, immortalised cell line with increased self-renewal capacity. Experiments in which the GM-CSF gene was inserted into normal haemopoietic cells has not yet been shown to be a primary leukaemogenic event.41 Similarly in transgenic GM-CSF mice although the macrophages transcribe and secrete GM-CSF, they do not undergo leukaemic transformation.42 Overall this data suggests that although the acquisition of autocrine growth characteristics may be important in

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leukaemogenesis, it is likely to be a late event rather than an early or initiating one.

Evidence for Autocrine

Growth of AML

Cells

In 1985, Young and Griffin reported two cases when the autonomous growth of AML blast cells was associated with the presence of GM-CSF transcripts on Northern analysis whereas they could not be detected in normal bone marrow mononuclear cells.” These cells also secreted GM-CSF and their growth could be inhibited by the addition of neutralising antibodies to GM-CSF, suggesting an extracellular autocrine loop. ‘i In a larger study GM-CSF mRNA was detected in 11 out of 22 AML samples and GMCSF was secreted, as detected by a bioassay in 6 of the 11 .43 Many other reports have confirmed these findings and have shown that transcripts for other cytokines including G-CSF, M-CSF, IL-l, IL-6 and TNFcl, as well as GM-CSF, are frequently detected.44P49 Oster et al44 found that 19 out of 28 AML samples which expressed GM-CSF transcripts, simultaneously co-expressed either IL-l 8, IL-6, TNFcl or G-CSF, however none of the samples had detectable levels of IL-3. Although many AML cells produce one or more haemopoietic growth factors as shown by Northern analysis or by detection of growth factor protein, only rare patients appear to have a rearranged growth factor gene.45,50 Young et al attempted to correlate the expression of CSF transcripts with autonomous growth in culture but found that there were many cases in which CSF transcripts were detected but autonomous growth was not observed.43q47 In contrast Reilly et all2 using a bioassay, were able to detect CSF production by all AML blasts that exhibited partial (group 3) or totally autonomous growth (group 4). These results have been confirmed by more recent studies where GM-CSF production has been measured using a sensitive and specific enzyme-linked immunosorbent assay. lo High levels of GM-CSF were secreted by all group 4 blasts (mean 2207 pg/106 cells), intermediate levels by group 3 blasts with partially autonomous growth (mean 270 pg/106 cells), whereas group 2 blasts which are CSF dependent, secreted minimal or undetectable GM-CSF. Thus the amounts of GM-CSF secreted closely correlated with the growth characteristics of the cells and explains the marked density-dependent growth of group 3 cells as being related to the cell concentration required to achieve a critical concentration of GM-CSF requisite to trigger proliferation. The variability in the data concerning the relationship between the presence of autonomous growth and autocrine growth factor production almost certainly reflects the culture conditions used to detect autonomous growth and the methods used to assay cytokine production. Certainly the use of relatively low density cultures will underestimate autonomous growth’2,‘3 and in the past have probably lead to an overemphasis on the depen-

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dency of human leukaemic cells on exogenous growth factors. In some, but not all of the blasts that produce GM-CSF, the autonomous proliferation can be inhibited by neutralising antibodies to GMCSF.“,12,‘3.51 Others can be inhibited by anti-GCSF suggesting that this cytokine can also act as an autocrine growth factor.13 Whether intracellular loops operate in AML blasts as well as leukaemic cell lines is more difficult to be certain. Certainly not all AML blasts which elaborate GM-CSF, are inhibited by GM-CSF antisera some they can be inhibited by antisense oligonucleotides to GM-CSF,52 thus providing further, although not conclusive evidence, for the existence of intracellular loops in some AML blasts. In contrast to GM- and G-CSF, M-CSF has not been implicated as an autocrine factor for AML blasts; indeed a significant association between M-CSF expression and poor growth in suspension culture has been reported.53 Studies with human erythroleukaemia cells have demonstrated that in these cells erythropoietin (Epo) is produced in an autocrine fasion.54 Erythropoietin transcripts were detected in 8 out of 13 cases studied and in one case it was clearly demonstrated that Epo was involved in extracellular autocrine stimulation and in another, studies with RNA antisense oligonucleotides suggested an intracellular mechanism.54

Interleukin-I

as an autocrine growth factor

in AML

Interleukin-1 has multiple effects on normal haemopoiesis including a direct effect on the proliferation of haemopoietic stem cells and induction of a number of cytokines including GM-CSF, G-CSF, M-CSF, IL-6 and IL-l from multiple cell types, including bone marrow stromal cells.55 The blast cells of some cases of AML proliferate in response to IL-l and although a direct effect may be operational in some cases,23 it was found that IL-l induced the production of GM-CSF by AML cells and the proliferative effect could be partially or totally inhibited by neutralising antibodies to GM-CSF,56-58 suggesting that the effects of IL-l were mediated by induction of autocrine GM-CSF. We found that blasts with partially autonomous growth (group 3) responded to IL-l whereas blasts which grew totally autonomously (group 4) could not be further stimulated by IL- 1.56 Interestingly some blasts which did not exhibit any in vitro autonomous growth (group 2) proliferated in response to IL-l and secreted high levels of GMCSF, indicating that even cells with apparently CSF dependent growth were capable of autocrine growth factor production in response to IL-l.56 Most of these studies have been carried out the FAB types M 1 to M5; recently studies with M7 (megakaryoblastic) blasts have demonstrated the presence of IL-6, but not GM-, G- or M-CSF, transcripts following IL-l treatment. These cells also secreted IL-6 protein when exposed to IL-l suggesting that IL-6 acts as an autocrine factor for leukaemic megakaryocytes.59

154 AUTOCTINE GROWTH FACTORS AND LEUKAEMIC HAEMOPOIESIS Not only do some AML blasts respond to IL-l but many express IL-l transcripts and secrete IL-la and IL- 113,46,60,61although there is evidence that II-lp is the molecular form most abundantly produced.61 Using in situ hybridisation, Nakamura et a16* detected IL-ll3 transcripts in between 1% and 40% of fresh, uncultured cells in 17 out of 19 cases of AML. The transcripts were detectable in undifferentiated cells with ‘blastic’ morphology rather than monocytoid leukaemic cells or contaminating monocytes. 62 Cozzolino et a16i found that IL-l activity could be detected intracytoplasmically in blasts from all of 13 patients studied and that antibodies to IL-l suppressed the autonomous growth of these cells, suggesting that IL-l, like GM-CSF, could act as an autocrine growth factor in AML. Using an ELISA we found that, like GM-CSF, IL-10 production is closely correlated with the growth characteristics of the cells.” Group 2 blasts produced no detectable IL-l p, with intermediate levels by group 3 blasts and high levels by group 4 blasts. The effect of IL-l antibodies on autonomous growth of AML blasts has now been clearly demonstrated to be due to the suppression of autocrine GM-CSF production.51r56*58,63This data suggests that endogenous IL-l acts as a component of a complex autocrine loop by regulating the production not only of autocrine GM-CSF but also G-CSF and IL-6 (see Fig. 3). IL-l not only functions as an autocrine growth factor in AML but may also induce paracrine secretion of GM-CSF, G-CSF and IL-6 by bone marrow stromal cells46 (see Fig. 3), suggesting a key hierarchic role for this cytokine in regulating AML cell growth by multiple autocrine and paracrine loops. In normal tissues, cytokine transcripts (including GM-CSF, G-CSF, IL-l and IL-6) are extremely short-lived with half-lives of 20 min-1 h.(j4p6’ This instability is thought to be in part mediated, by AU rich sequences in the 3’ untranslated region of the mRNA leading to susceptibility to RNase cleavage.@j The half-life of GM-CSF mRNA can be prolonged by a number of mechanisms including treatment with

IL- 154TNFIx~~ and the expression of ras oncogenes.67 In contrast to normal cells, GM-CSF and other cytokine transcripts from tumour cell line@* and AML blast@’ have enhanced stability with half-lives increased several fold. Thus the high levels of growth factor production, characteristic of many AML blasts, may be mediated by the enhanced cytokine transcript stability seen in these cells. It is therefore possible that constitutive production of IL-l may account for the enhanced GM-CSF transcript stability and GM-CSF protein secretion seen in myeloid leukaemia cells although other mechanisms may exist. Does autocrine growth have any clinical relevance in AML? We have recently analysed our own data concerning the effects of growth characteristics on treatment outcome in AML (Hunter et al, in preparation). We found that patients whose blast cells exhibited partially or totally autonomous growth (groups 3 and 4) had significantly lower complete remission rates and reduced survival compared to group 1 and 2 patients. Can drugs be developed to suppress autocrine growth in vivo? This approach is particularly attractive as there is no conclusive evidence for equivalent autocrine loops operating in normal haemopoiesis. Normal bone marrow cells, including purified CD34 positive cells, do not grow autonomously in culture, although there is some evidence to suggest that CD34 positive cells produce GM-CSF in response to IL- 1.” One development of interest in this area is the use of agents which block IL-l activity. As outlined above IL-l has a key role in the proliferation of AML blasts in vitro. Recently recombinant IL-l receptor antagonist (IL-lra), a molecule which specifically blocks IL-l binding to its cell surface receptors without demonstrable agonist activity,‘i has been shown to suppress the blast cell proliferation from a number of patients with AML72,73 whereas no effect was apparent against normal bone marrow precursors. IL-lra is now entering clinical trial in a variety of conditions without showing major side-effects and this agent may be of value in the treatment of AML.

G.CSF

Fig. 3 Involvement of interleukin-1 in leukaemic haemopoiesis. Loop 1: IL-l produced by AML blasts regulates autocrine production of GM-CSF, G-CSF and IL-6 (and possibly of IL-l itself). Loop 2: IL-l induces paracrine production of these factors by bone marrow stromal cells.

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However, autocrine growth loops can be disrupted at multiple sites74 and the definition of their importance in in the proliferation of AML cells offers the possibilities of developing novel therapies for this disease.

Acknowledgement I would like to thank Dawn Bradbury for helpful discussion in preparing this manuscript and the Leukaemia Research Fund for supporting some of the work described here.

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AUTOCTINE

GROWTH

FACTORS

AND

LEUKAEMIC

polyoma middle T. antigen parallels that of primary human myeloid leukemic cells. EMBO Journal 6: 3703-3709 Duhrsen U 1988 In vitro growth patterns and autocrine production of hemopoietic colony stimulatory factors; Analysis of Leukemic populations arising in irradiated mice from cells of an injected factor-dependent continuous cell line. Leukemia 2: 334-342 Dunn A R, Wilks A F 1990 Contributions of autocrine and non-autocrine mechanisms of tumorigenicity in a murine model for leukaemia. In Molecular control of haemopoiesis. Wiley Chichester (Ciba Foundation Symposium 148) 145-157 Johnson G R, Gonda R J, Metcalf D, Hariharan I K, Cory S 1989 A lethal myeloproliferative syndrome in mice transplanted with bone marrow cells infected with a retrovirus expressing granulocyte-macrophage colony stimulatory factor. EMBO Journal 8: 441-448 Larry R, Metcalf D, Cuthbertson R A et al 1987 Transgenic mice expressing a hemopoietic growth factor gene (GMCSF) develop accumulations of macrophages, blindness and a fatal syndrome of tissue damage. Cell 51: 675-686 Young D C, Wagner K, Griffin J D 1987 Constitutive expression of the granulocyte-macrophage colony stimulating factor gene in acute myeloblastic leukemia. Journal of Clinical Investigation 79: 200-206 Oster W, Cicco N A, Klein H et al 1989 Participation of cytokines interleukin-6, tumour necrosis factor-alpha and interleukin-l-beta secreted by acute myelogenous leukemia blasts in autocrine and paracrine leukemia growth control. Journal of Clinical Investigation 84: 45 l-457 Cheng G Y M, Kelleher C A, Miyaudii J et al 1988 Structure and expression of genes of GM-CSF and G-CSF in blast cells from patients with acute myeloblastic leukemia. Blood 71: 35-41 Griffin J D, Rambaldi A, Vellenga E, Young D C, Ostapovicz, Cannistra S A 1987 Secretion of Interleukin-1 by acute myeloblastic leukemia cells in vitro induces endothelial cells to secrete colony stimulating factors. Blood 70: 1218-1221 Young D C, Demetri G D, Ernst T J, Cannistra S, Griffin J D 1988 In vitro expression of colony stimulating factor genes by human acute myeloblastic leukemia cells. Exnerimental Haematoloav 16: 378-382 Kaufman D, Baer M, Gay X Z, Wang Z, Preisler H D 1988 Enhanced expression of granulocytes-macrophage colony stimulating factor genein acute myeloblastic leukemia cells following in vitro blast cell enrichment. Blood 72: 1329-1332 Van der Schoot C, Jansen P, Poorter M et al 1989 Interleukin-6 and interleukin-1 production in acute leukemia with monocytoid differentiation. Blood 74: 2081-2087 Falcinelli F, Onorato M, Falzetti F et al 1991 Activation of the granulocyte-monocyte colony stimulating factor gene in acute myeloid leukemia cells is not related to gene rearrangement. Leukemia Research 15: 957-961 Rodriauez-Cimadevilla J C. Beauchemin V, Villeneuve L. Letendre F, Shaw A, Hoang T 1990 Co-ordinate secretion of interleukin- 1g and granulocyte macrophage colony stimulating factor by the blast cells of acute myeloblastic leukemia: Role of Interleukin-1 as an endogenous inducer. Blood 76: 1481-1489 Rogers S, Bradbury D, Kozlowski R, Russell N H 1991 Mechanism of autonomous growth in acute myeloid leukemia cells. Evidence of intracellular and extracellular autocrine and naracrine 100~s. Blood 78: SUDD~: 1 1053 Wang C, Kelleher C A, Cheng G Y M et al-1988 Expression of the CSF-1 gene in the blast cells of acute myeloblastic leukemia: Association with reduced growth capacity. Journal of Cellular Physiology 135: 133-138 Mitjavila M T, Le Covedic J P, Casadevall N et al 1991 Autocrine stimulation by erythropoietin and autonomous growth of human erythroid leukaemia cells in vitro. Journal of Clinical Investigation 88: 789-797 Bagby G C 1989 Interleukin-1 and haematopoiesis. Blood Reviews 3: 152-161

HAEMOPOIESIS 56. Bradbury D, Rogers S, Kozlowski R, Bowen G, Reilly I A G, Russell N H 1990 Interleukin-1 is one factor which regulates the autocrine production of GM-CSF by blast cells of acute myeloblastic leukaemia. British Journal of Haematology 76: 488-493 57. Delwel R, van Buitenen C, Salem S et al 1989 Interleukin-1 stimulates proliferation of acute myeloblastic leukemia cells by induction of granulocyte-macrophage colony-stimulating factor release. Blood 74: 586-593 I, Tohda S, Suzuki T, Nagata K, Yamashita Y, 58. Murohashi Nara N 1990 Mechanism of action of interleukin-1 on the progenitors of blast cells in acute myeloblastic leukemia. Experimental Haematology 18: 133-137 L, Schwulera U, 59. Brach M A, Lowenberg B, Mantovani Mertelsmann R, Herrman F 1990 Interleukin-6 (IL-6) as an intermediate in IL-l-induced proliferation of leukemic human meaakarvoblasts. Blood 76: 1972-1979 M, Asov N, Yamamoto S, 60. Sakai K, Hatton T, Matsuoka Sagawa K, Takatsuki I 1987 Autocrine stimulation of Interleukin 1S in acute myelogenous leukemia cells. Journal of Experimental Medicine 166: 1597-1602 61. Cozzolino F, Rubartelli A, Aldinucci D 1989 Interleukin-1 as an autocrine growth factor for acute myeloid leukemia cells. Proceedings of National Academy of Sciences of USA. 86: 2369-2373 M, Kanakura Y, Furukawa Y, Ernst T J, 62. Nakamura Grillin D 1990 Demonstration of Interleukin-IS transcripts in acute myeloblastic leukemia cells by in situ hybridisation. Leukemia 44: 466-470 63. Bradbury D, Bowen G, Kozlowski R, Reilly I A G, Russell N H 1990 Endogenous interleukin-1 can regulate autonomous growth of acute myeloblastic leukemia and by inducina autocrine secretion of GM-CSF. Leukemia 4: 44-47 Z, Koeffler H P 1989 Regulation of 64. Yamato K, El-Hajjaoui IL-l mRNA in human fibroblast. Journal of Cellular Physiology 139: 610-616 Z, Kuo J F, Koeffler H P 1989 65. Yamato K, El-Hajjaoui Granulocyte-macrophage colony-stimulating factor: Signals for its mRNA accumulation. Blood 74: 1314-1320 66. Shaw G, Kamen R 1986 A conserved AU sequence from the 3r untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 46: 659-668 67. Demetri G, Ernst T J, Pratt E S, Zenzie B W, Rheinwald J G, Griffin J D 1989 Expression of ras oncogenes in cultured human cells alters the transcriptional and posttranscriptional regulation of cytokine genes. Journal of Clinical Investigation 86: 1261-1269 68. Ross H J, Sata N, Veyama Y. Koeffler H P 1991 Cytokine messenger RNA stability in enhanced in tumour cells. Blood 77: 1787-1795 R, Griffin J D 1989 69. Ernst T J, Ritchie A R, O’Rourke Colony-stimulating factor gene expression in human acute myeloblastic leukemia cells is post-transcriptionally regulated. Leukemia 3: 620-625 K, 70. Bot F J, Schipper P, Broeders L, Delwel R, Kauchansky Lowenberg B 1990 Interleukin-la also induces granulocytemacronhaae colony-stimulating factor in immature normal bone marrow cells: Blood 76: 307-311 R 1991 Blocking IL-l: interleukin 1 71. Dinarello C. Thomnson receptor antagonist-in vivo and in vitro. immunology Today 12: 404-410 of cell 72. Rambaldi A, Torcia M, Bettoni St 1991 Modulation proliferation and cytokine production in acute myeloblastic leukemia by inter&kin-l receptor antagonist and lack of its expression bv leukemic cells. Blood 78: 3248-3253 73. Esirov Z, Kuzrock R, Estey E 1992 Inhibition of acute myelogenous leukemia blast proliferation by interleukin- 1 (IL-l) receptor antagonist and soluble IL-l receptors. Blood 79: 1938-1945 Blake S 1992 Therapeutic potential of cytokine 74. Henderson, manipulation. Trends in Pharmaceutical Science 13: 145-152

Autocrine growth factors and leukaemic haemopoiesis.

Studies on the structure of haemopoiesis in acute myeloblastic leukaemia (AML) has shown the presence of a small population of malignant cells with ex...
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