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REVIEW Signal Transduction, Cell Cycle Regulatory, and Anti Leukemia (1999) 13, 1109–1166 1999 Stockton Press All rights reserved 0887-6924/99 $12.00 http://www.stockton-press.co.uk/leu REVIEW Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs WL Blalock1, C Weinstein-Oppenheimer1,2, F Chang1, PE Hoyle1, X-Y Wang3, PA Algate4, RA Franklin1,5, SM Oberhaus1,5, LS Steelman1 and JA McCubrey1,5 1Department of Microbiology and Immunology, 5Leo Jenkins Cancer Center, East Carolina University School of Medicine Greenville, NC, USA; 2Escuela de Quı´mica y Farmacia, Facultad de Medicina, Universidad de Valparaiso, Valparaiso, Chile; 3Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, MN, USA; and 4Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Over the past decade, there has been an exponential increase growth factor), Flt-L (the ligand for the flt2/3 receptor), erythro- in our knowledge of how cytokines regulate signal transduc- poietin (EPO), and others affect the growth and differentiation tion, cell cycle progression, differentiation and apoptosis. Research has focused on different biochemical and genetic of these early hematopoietic precursor cells into cells of the 1–4 aspects of these processes. Initially, cytokines were identified myeloid, lymphoid and erythroid lineages (Table 1). This by clonogenic assays and purified by biochemical techniques. review will concentrate on IL-3 since much of the knowledge This soon led to the molecular cloning of the genes encoding of how cytokines affect cell growth, signal transduction, and the cytokines and their cognate receptors. Determining the apoptosis has been elucidated from research with IL-3-depen- structure and regulation of these genes in normal and malig- nant hematopoietic cells has furthered our understanding of dent cell lines. Some other cytokines (eg GM-CSF and IL-5) neoplastic transformation. Furthermore, this has allowed the exert their effects through similar mechanisms. design of modified cytokines which are able to stimulate mul- IL-3 was initially defined by its ability to induce the enzyme tiple receptors and be more effective in stimulating the repopu- 20-␣-hydroxysteroid dehydrogenase in cultures of splenic lation of hematopoietic cells after myelosuppressive chemo- lymphocytes from nude mice.5 However, it soon became therapy. The mechanisms by which cytokines transduce their regulatory signals have been evaluated by identifying the apparent that IL-3 was being studied by a number of investi- involvement of specific protein kinase cascades and their gators under a variety of aliases. It was called persisting cell- downstream transcription factor targets. The effects of cyto- stimulating factor (PSF),6 mast cell growth factor (MCGF),7 kines on cell cycle regulatory molecules, which either promote hematopoietic cell growth factor (HCGF),8 histamine-produc- or arrest cell cycle progression, have been more recently exam- ing cell-stimulating factor,9 multi-colony stimulating factor ined. In addition, the mechanisms by which cytokines regulate 10 5 apoptotic proteins, which mediate survival vs death, are being (multi-CSF), Thy-1-inducing factor, and burst promoting 11 elucidated. Identification and characterization of these com- activity (BPA). All of these growth stimulatory activities were plex, interconnected pathways has expanded our knowledge of subsequently identified as the same protein and renamed IL-3. leukemogenesis substantially. This information has the poten- IL-3 was shown to act on both myeloid and lymphoid lin- tial to guide the development of therapeutic drugs designed to eages by in vitro studies. In vivo administration of pharmaco- target key intermediates in these pathways and effectively treat patients with leukemias and lymphomas. This review focuses logical doses of recombinant IL-3 to mice resulted in the on the current understanding of how hematopoietic cytokines increased production of red blood cells, leukocytes and plate- such as IL-3, as well as its cognate receptor, are expressed and lets.12 Moreover, over-expression of the IL-3 gene in hemato- the mechanisms by which they transmit their growth regulatory poietic progenitors via retroviral transduction of bone marrow signals. The effects of aberrant regulation of these molecules cells resulted in a non-neoplastic, myeloproliferative syn- on signal transduction, cell cycle regulatory and apoptotic 13 pathways in transformed hematopoietic cells are discussed. drome in vivo. Finally, anti-neoplastic drugs that target crucial constituents in To further understand the role of IL-3 in vivo, transgenic these pathways are evaluated. mice expressing antisense IL-3 RNA were created. These Keywords: cytokines; signal transduction; anti-neoplastic drugs; mice, which exhibited decreased serum levels of IL-3, oncogenes; apoptosis developed either a B cell lymphoproliferative syndrome or a neurological dysfunction.14 In more recent studies with IL-3- deficient mice, a role for IL-3 in contact hypersensitivity was Cytokines and hematopoiesis observed. IL-3 was determined to be necessary for efficient priming of hapten-specific contact hypersensitivity.15 Cytokines stimulate cell cycle progression, proliferation, and IL-3 transgenic mice have also been used to examine the differentiation, as well as inhibit apoptosis of hematopoietic 1–3 effects of constitutive IL-3 expression on development and cells. Peripheral blood cells are generated from self-renew- neoplasia. Recent evidence indicative of neurological dys- able, pluripotential hematopoietic stem cells in the bone function in IL-3-transgenic mice supports the idea that this marrow. Cytokines such as interleukin-3 (IL-3), hematopoietic cytokine performs key roles in the central ner- granulocyte/macrophage colony stimulating factor (GM-CSF), vous system as well.14–19 The pleiotropic roles of this cytokine stem cell factor (SCF, or steel factor, c-Kit-L, macrophage must be considered when therapies are developed based upon alteration of IL-3 expression, down-regulation of cognate Correspondence: JA McCubrey, Department of Microbiology and receptor expression and function, or destruction of IL-3 recep- Immunology, East Carolina University School of Medicine, Brody tor (IL-3R)-positive cells by chimeric IL-3-toxin molecules. Building 5N98C, Greenville, NC 27858, USA; Fax: 252-816-3104 Received 2 March 1999; accepted 14 May 1999 Review WL Blalock et al 1110 Table 1 Abbreviations of cytokines, growth factors, their receptors and cellular targets Abbreviation Full name Target cells or function EGF Epidermal growth factor Affects the growth of many cells epo Erythropoietin Erythroid cells flt-2/flt-3L Ligand for the flt2/flt3 receptor Early hematopoietic progenitor cells G-CSF Granulocyte-colony stimulating Granulocyte/monocyte progenitor cells factor GM-CSF Granulocyte/macrophage- Many early hematopoietic precursor cells of the myeloid lineage, neutrophilic colony stimulating factor granulocytes, monocyte–macrophages, eosinophils; has the ability to activate macrophages gp130 Glycoprotein 130 Signal transducing receptor protein shared among IL-6, LIF, oncoM and other cytokines IL-3 Interleukin-3 Many early hematopoietic precursor cells of both myeloid and lymphoid lineages IL-3R Interleukin-3 receptor Present on many early hematopoietic cells IL-4 Interleukin 4 B cells, mast cells, some T cells IL-5 Interleukin 5 B cells, eosinophils LIF Leukemia inhibitory factor Homology with oncoM, inhibits proliferation of tumor cell lines, affects a broad range of cells M-CSF Macrophage-colony stimulating Granulocyte–monocyte progenitor, receptor is the product of the c-fms proto- factor oncogene oncoM Oncostatin M 28-kDa protein with homology to LIF, inhibits proliferation of tumor cell lines, affects a broad range of cells, expression induced by Jak/STAT pathway SCF Stem cell factor, also known as Many early hematopoietic cells, receptor is the product of the c-kit proto-oncogene, c-kit ligand stimulates proliferation of myeloid, erythroid and lymphoid progenitors TGF-␤ Transforming growth factor-beta Often inhibits cell proliferation, wide tissue distribution TPO Thrombopoietin Growth and differentiation factor for megakaryocytes, receptor is the c-mpl proto- oncogene Recombinant/chimeric cytokines and therapy tration of daniplestim and G-CSF results in higher numbers of short-term and long-term clonogenic cells compared to A variety of engineered recombinant cytokines are currently sequential administration of daniplestim and G-CSF.29 In the under investigation for use in hematopoietic reconstitution of rhesus myelosuppression model, daniplestim accelerated patients undergoing myelosuppressive chemotherapy hematopoietic reconstitution in radiation-induced cytopenia. (Table 2).20–47 A fusion molecule containing IL-3 and GM-CSF Daniplestim significantly reduced the nadir of neutropenia (PIXY 321) developed by Immunex activates both the IL-3 and and the duration of thromocytopenia in animals with radi- GM-CSF receptors.22–25 ation-induced myelosuppression.27 Taken together, these data GD Searle Pharmaceuticals has developed a structurally and suggested that daniplestim may be clinically useful in patients functionally distinct IL-3 receptor agonist (daniplestim) which with chemotherapy-induced myelosuppression and support binds to the IL-3 receptor with higher affinity than native IL- the utility of combination therapy. 3 but has reduced inflammatory
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