HEMATOPOIESIS is governed by a number of cytokines that promote the survival, proliferation, and differentiation of hematopoietic stem cells and progenitor cells.1 Stem cell factor (SCF; also known as kit ligand, mast cell growth factor, or steel factor) is a hematopoietic cytokine that triggers its biologic effects by binding to its receptor, c-kit.2-5 A host of naturally occurring mutations at the Sl locus or at the W locus, which encode SCF and the c-kit receptor, respectively, has been identified6,7 and molecularly characterized (reviewed in Besmer et al8 ). These mutations provide insights into the role of SCF and the c-kit receptor in vivo. Absence of SCF protein (the Sl mutation) or absence of cell surface c-kit receptor display (the W mutation) result in death in utero or in the perinatal period with severe macrocytic anemia. Absence of c-kit receptor kinase activity (the W42 mutation)9 also causes perinatal death with severe macrocytic anemia. These observations indicate that SCF plays an essential role during development in utero.

Point mutations in the c-kit receptor that diminish its tyrosine kinase activity or mutations that alter SCF production are associated with a spectrum of phenotypic abnormalities, including variable degrees of macrocytic anemia, decreased numbers of tissue mast cells, decreased fertility, and decreased pigmentation.10 These observations demonstrate a role for SCF and its receptor c-kit in hematopoiesis and in development of germ cells and melanocytes. Development of the interstitial cells of Cajal, which are responsible for intestinal pacemaker activity, is defective in mice with mutations at the Sl or W loci.11,12 In general, the severity of the defect in c-kit receptor kinase activity parallels the severity of the phenotypic abnormalities that result.13 

SCF is normally found in both soluble and transmembrane forms14 (Fig 1, described in detail below). The Sld mutation (deletion of the transmembrane and cytoplasmic domains of SCF ) results in production of soluble SCF and absence of transmembrane SCF.14,15,Sl/Sld mice are viable, but have severe macrocytic anemia, markedly reduced tissue mast cells, and are sterile and white.6 The phenotype of the Sl/Sld mouse indicates that the presence of soluble SCF is not sufficient to completely compensate for the lack of transmembrane SCF and suggests that the transmembrane form of SCF may play a unique role in vivo.

Fig. 1.

Soluble and transmembrane forms of human SCF. The primary proteolytic cleavage site of SCF248 in exon 6 is indicated by the arrow. Cleavage at this site generates the soluble form of SCF. The transmembrane form of SCF, SCF220, lacks the primary proteolytic cleavage site in exon 6. The 25 amino acid signal sequence (dotted lines) and the hydrophobic transmembrane domain (dark box) are also shown. As described in the text, murine SCF248 and murine SCF220 can also be cleaved at an alternative site in exon 7.

Fig. 1.

Soluble and transmembrane forms of human SCF. The primary proteolytic cleavage site of SCF248 in exon 6 is indicated by the arrow. Cleavage at this site generates the soluble form of SCF. The transmembrane form of SCF, SCF220, lacks the primary proteolytic cleavage site in exon 6. The 25 amino acid signal sequence (dotted lines) and the hydrophobic transmembrane domain (dark box) are also shown. As described in the text, murine SCF248 and murine SCF220 can also be cleaved at an alternative site in exon 7.

During embryonic life, SCF and c-kit receptor RNA are expressed along the migratory pathways and in destinations of primordial germ cells and melanocytes, in sites of hematopoiesis (including the yolk sac, fetal liver, and bone marrow), in the gut, and in the central nervous system.16-18 This pattern of expression suggests that SCF may influence the migration of germ cells, melanocytes, and hematopoietic cells to their ultimate destinations during development. Hematopoietic cells expressing the c-kit receptor protein were detected at gestational day 8 in the embryonic yolk sac and by day 10 in fetal liver, where they progressively increased until day 15 and then decreased,19 paralleling the transition from yolk sac to fetal liver to bone marrow hematopoiesis. Fetal thymus also contains c-kit receptor-positive primitive T-lymphocyte and B-lymphocyte progenitors.19 Although the brain and spinal cord develop normally in mice with mutations at the Sl or W loci, these mice demonstrate subtle learning and memory defects.20 

In addition to its essential role during development, SCF is also important during adult life. Treatment of adult mice with a neutralizing anti–c-kit receptor monoclonal antibody (ACK2) causes pancytopenia and markedly decreases bone marrow cellularity,21 suggesting that constitutive production of SCF by marrow endothelial cells and fibroblasts22,23 may be required for maintenance of normal basal hematopoiesis. SCF is also required for acute erythroid expansion during recovery from hemolytic anemia in adult mice.24 Spermatogenesis,25 melanocyte development,26 gut motility,12 and response to intestinal helminth infection27 are impaired by ACK2 antibody treatment.

This review will briefly discuss the production and structure of SCF and will focus on the physiologic role of SCF in hematopoiesis. The cellular distribution of the c-kit receptor will also be described. Potential clinical uses for SCF and therapeutic approaches based on the c-kit receptor will be discussed.

SCF PRODUCTION

SCF is encoded by the Sl locus on mouse chromosome 104,5,28 and has been mapped to human chromosome 12q22-12q24.29,30 The structural organization of the SCF gene has been recently reviewed.31 

The soluble and transmembrane forms of SCF are generated by alternative splicing that includes or excludes a proteolytic cleavage site (Fig 1).29,32 Both the soluble and the transmembrane form of SCF are biologically active.33,34 SCF248 includes exon 6, which encodes a proteolytic cleavage site, resulting in the production of soluble SCF. The cleavage occurs after Ala165. The lack of exon 6 in human SCF220 results in production of the transmembrane form of human SCF. In SCF220, amino acids 149-177 are replaced by a Gly residue. The ratio of SCF248 mRNA to SCF220 mRNA varies considerably in different tissues, ranging from 10:1 in the brain and 4:1 in the bone marrow to 0.4:1 in the testis.32,35 Studies of normal human bone marrow fibroblasts confirm that these marrow stromal cells contain predominantly SCF248 mRNA.23 The mechanisms that control the tissue-specific32 and developmentally regulated36 production of SCF248 vs SCF220 are not well understood.

Soluble murine SCF can be generated by cleavage of murine SCF248 at the site in exon 6 or by cleavage of murine SCF248 or murine SCF220 at an alternative site in exon 7. A fibroblast cell line (Sl/Sl4 ), derived from the liver of a fetal Sl/Sl mouse that contains no SCF mRNA,34 was engineered to express murine SCF248 or murine SCF220.37 Both the Sl/Sl4murine SCF248 and the Sl/Sl4murine SCF220 cell lines were found to produce soluble SCF,37 suggesting the existence of a secondary proteolytic cleavage site for murine SCF.32,37 Deletion of 12 nucleotides (encoding Lys178-Lys181 ) in exon 7 of murine SCF prevented release of soluble SCF, thus identifying a second proteolytic cleavage site that is unique to murine SCF.

The cleavage of SCF from the cell surface can be induced by activation of protein kinase C or by agents that increase cytosolic calcium levels.32 Two serine protease inhibitors prevented the cleavage of murine SCF248 but not that of murine SCF220, suggesting that cleavage at the sites in exon 6 and exon 7 may be differentially regulated.38 However, certain protease inhibitors affect protein transport to the cell surface rather than protein cleavage at the cell surface, and a recent report suggests that a family of metalloproteases may release the soluble form of many cell surface proteins.39 

SCF is constitutively produced by endothelial cells and by fibroblasts.22,23,40 These cells display the transmembrane form of SCF on the cell surface and also release soluble SCF. Keratinocytes in normal skin41 and epithelial cells in the gut42,43 produce SCF, and SCF protein can be detected in the thymus44 as well as in other sites.45-47 Enriched populations of human hematopoietic stem cells and progenitor cells (CD34+c-kit receptor+) are reported to contain SCF mRNA detectable by reverse transcription polymerase chain reaction.48 Inflammatory stimuli such as interleukin-1 (IL-1) or tumor necrosis factor (TNF ) may modestly enhance SCF protein production by marrow stromal cells,22,23 in contrast to their profound ability to increase granulocyte-macrophage colony-stimulating factor (GM-CSF ) and granulocyte colony-stimulating factor (G-CSF ) production.49 Exposure of endothelial cells to transforming growth factor β1 (TGFβ1 ) can decrease SCF mRNA content and SCF production in vitro.50 

The concentration of SCF in normal human serum is, on average, 3.3 ng/mL.51 Studies of patients with aplastic anemia, myelodysplasia, and a number of other types of chronic anemia have shown no increase in serum SCF levels.52-54 Thus, the level of SCF in the circulation, unlike the level of erythropoietin (Epo), is not inversely related to the hematocrit. Serum SCF levels do not increase during the period of profound pancytopenia in patients undergoing marrow ablative chemoradiotherapy and stem cell transplantation.55 Myelosuppressive chemotherapy or radiation therapy can increase SCF mRNA levels in murine bone marrow,56,57 but whether this results in increased display of the transmembrane form of SCF within the marrow microenvironment is not known. Alterations in the local distribution of SCF within the skin have been described in patients with cutaneous mastocytosis41 and may play a role in the pathogenesis of this disorder.

SCF STRUCTURE

The soluble form of SCF circulates as a noncovalently bonded dimer, is glycosylated, and has considerable secondary structure, including regions of α helices and β sheets.5,58-60 The molecular weight of the soluble form of SCF calculated from its amino acid sequence is approximately 18,500 daltons. Expression of SCF in Chinese hamster ovary cells results in proteins of 28,000 to 40,000 daltons, indicating the presence of extensive and heterogenous glycosylation.58,61 Human SCF expressed in Chinese hamster ovary cells is approximately 30% carbohydrate by weight58 and contains both N-linked and O-linked carbohydrate, both with attached sialic acid. The glycosylation sites of SCF have been characterized in detail.62 

The 4 Cys residues of SCF are involved in intramolecular disulfide bonds62 (Fig 2). The disulfide pairs are Cys4-Cys89 and Cys43-Cys138. Truncation mutagenesis of the carboxy-terminal region of soluble SCF reveals that biologic activity is diminished when the region containing Cys138 is deleted, suggesting that the Cys43-Cys138 bond may be important for full biologic activity63; subsequent work suggests that both intramolecular disulfide bonds are critical to maintain SCF in a fully biologically active conformation.64 Although an active dimeric form of SCF with 4 intermolecular disulfide bonds has been identified during oxidation and refolding of recombinant SCF expressed in Escherichia coli,65 neither Chinese hamster ovary-expressed SCF nor native SCF dimers have been reported to contain intermolecular disulfide bonds, so it seems unlikely that this form of SCF plays a major role in vivo.

Fig. 2.

A molecular model of human SCF structure. The model is based extensively on the published structure of human M-CSF (Modified and reprinted with permission from Pandit et al.69 Copyright 1992 American Association for the Advancement of Science.) and the M-CSF/SCF alignment of Bazan.66 The SCF four helix bundle with two long overhand loops is shown as a ribbon diagram. The location of the two intramolecular disulfide bonds is shown in yellow, and the helix boundaries are indicated in the single amino acid code. The interhelical loop lengths have been altered from the M-CSF structure to account for the slightly longer predicted loops of SCF. Tyr26 may be part of the dimer interface for SCF; this residue corresponds to Cys31 of M-CSF, the site of the single M-CSF interchain disulfide bond (Cys31-Cys31 ).

Fig. 2.

A molecular model of human SCF structure. The model is based extensively on the published structure of human M-CSF (Modified and reprinted with permission from Pandit et al.69 Copyright 1992 American Association for the Advancement of Science.) and the M-CSF/SCF alignment of Bazan.66 The SCF four helix bundle with two long overhand loops is shown as a ribbon diagram. The location of the two intramolecular disulfide bonds is shown in yellow, and the helix boundaries are indicated in the single amino acid code. The interhelical loop lengths have been altered from the M-CSF structure to account for the slightly longer predicted loops of SCF. Tyr26 may be part of the dimer interface for SCF; this residue corresponds to Cys31 of M-CSF, the site of the single M-CSF interchain disulfide bond (Cys31-Cys31 ).

Fig. 4.

Autoradiographic analysis of 125I-SCF binding to a normal human megakaryocyte. A multitude of grains is associated with the megakaryocyte, indicating that these cells display the c-kit receptor.

Fig. 4.

Autoradiographic analysis of 125I-SCF binding to a normal human megakaryocyte. A multitude of grains is associated with the megakaryocyte, indicating that these cells display the c-kit receptor.

SCF shares a number of features with macrophage colony-stimulating factor (M-CSF ),66 including dimeric structure, the existence of soluble and transmembrane forms generated by alternative splicing of a proteolytic cleavage site in exon 6, homologous intramolecular disulfide bonds, and homology between their receptors, c-kit and c-fms.67,68 M-CSF contains 3 additional Cys residues (beyond the 4 Cys residues found in SCF ), one of which is involved in an intermolecular disulfide bond between the two M-CSF monomers.69 It has been speculated that the relatively large area of contact at the surface of the two SCF monomers, even in the absence of an intermolecular disulfide bond, may suffice for stable dimer formation.69 Whether the transmembrane form of SCF is a dimer like the soluble form of SCF, is not known.

Rat and human SCF have roughly equivalent bioactivity on human hematopoietic cells, but rat SCF is 800-fold more active on a murine cell line than is human SCF.70 Rat SCF has a 100-fold higher binding affinity for the murine c-kit receptor than does human SCF.71 These observations have permitted the use of interspecies chimera to investigate the sequences of SCF required for bioactivity.72 Regions of the first, third, and fourth helices of SCF have been implicated as being essential for biologic activity.72 A splicing defect in the cytoplasmic tail of SCF in Sl/Sl17H mice results in male sterility,73 suggesting that an intact cytoplasmic domain of SCF may be important for normal function, although this mutation may also alter the stability of transmembrane SCF.

Amino-terminal and carboxy-terminal truncation of soluble human SCF has identified amino acids 1-141 as being essential for full biologic activity in vitro, assessed by ability to support proliferation of a factor-dependent cell line and ability to competitively displace binding of 125I-SCF1-165 to the c-kit receptor.74 Absence of amino acids 1-3 partially impaired both cell proliferation and receptor binding activity, whereas deletion of amino acid 4 or beyond completely ablated both activities. It is of interest that SCF truncation mutant 1-127 retained full receptor binding activity but had reduced ability to support cell proliferation, suggesting that receptor binding and receptor activation can be dissociated.74

SCF AND HEMATOPOIESIS

Elizabeth Russell first suggested that the W and Sl loci might encode a receptor-ligand pair that was critical for hematopoiesis in vivo.6 The seminal observations that marrow from W mutant mice could not reconstitute hematopoiesis when transplanted into irradiated hosts,75 that Sl marrow microenvironmental cells could not fully support hematopoiesis in vitro,76 and that transplantation of normal splenic tissue into Sl/Sld mice improved hematopoiesis77,78 indicated that the W defect was intrinsic to hematopoietic cells, whereas the Sl defect was intrinsic to marrow and splenic microenvironmental cells. The marrows of W/Wv and Sl/Sld mice contain fewer colony-forming units-spleen (CFU-S; W/Wv), burst-forming unit-erythroid (BFU-E), colony-forming unit–granulocyte-macrophage (CFU-GM), and colony-forming unit-erythroid (CFU-E) than do littermate controls.79-83 Subsequent studies in vitro have shown that SCF acts on hematopoietic stem cells and progenitor cells and, in some lineages, precursor cells and mature cells as well.

SCF can act directly on an enriched population containing hematopoietic stem cells to accelerate their entry into cell cycle.84 SCF alone transiently maintained the long-term repopulating ability of Rhodaminelow, Lin, Sca-1+ populations of murine hematopoietic cells, suggesting that SCF can promote the survival of hematopoietic stem cells in vitro.85 Self-renewal of stem cells in vitro in the presence of SCF alone or in the presence of SCF, IL-6, and Epo was not found.85,86 Stem cells can survive on a stromal cell line even in the presence of the ACK2 anti–c-kit receptor antibody, suggesting that other cytokines produced by the stromal cells can support stem cell survival in the absence of SCF activity.87 Brief exposure of murine marrow cells to a cytokine cocktail (SCF, IL-3, IL-6, and IL-11) expanded the number of progenitor cells but impaired long-term repopulating ability, sounding a cautionary note for ex vivo expansion protocols.88 Inclusion of IL-3 in a combination of growth factors used for ex vivo expansion reduced the B- and T-lymphocyte potential and the long-term reconstituting ability of murine hematopoietic cells,89-91 suggesting that IL-3 can promote differentiation at the expense of maintenance of true stem cell activity. However, murine marrow cells cultured in SCF plus IL-11 retained long-term repopulating activity and could be serially transplanted up to quartenary recipients.92 Sustained stem cell self-renewal in vivo may also be dependent on SCF.93 

Cells that give rise to spleen colonies in vivo (CFU-S) survive in vitro in the presence of SCF, and SCF in conjunction with IL-3 can increase the production of CFU-S over a 2-week period in vitro.94 Blocking the c-kit receptor with the ACK2 antibody markedly reduced the survival of CFU-S in vitro,95 although cells capable of initiating long-term bone marrow cultures (LTBMC-IC; defined by the ability to generate CFU-GM over a 5-week period in vitro) survived. Sl/Sl and normal fibroblasts supported LTBMC-IC equivalently, arguing that SCF is not required for LTBMC-IC survival.96 Human LTBMC-IC underwent self renewal and 50-fold expansion in the presence of a cytokine cocktail that, for optimal LTBMC-IC expansion, included SCF.97 

SCF, in concert with IL-3 or other cytokines, increased the number of BFU-E, CFU-GM, and colony-forming unit granulocyte, erythroid, macrophage, megakaryocyte (CFU-GEMM) produced approximately 20-fold in liquid culture over a 1- to 4-week period in vitro,98,99 indicating that SCF can act on a more primitive cell (pre–CFU-C) capable of generating the direct colony-forming cells. These observations98-101 have formed the basis for ex vivo expansion protocols for human hematopoietic progenitor cells. Combinations of 5 cytokines (SCF, Epo, IL-1, IL-3, and IL-6) resulted in up to a 200-fold expansion of BFU-E, CFU-GM, and CFU-GEMM over a 2-week period in vitro from mobilized human peripheral blood CD34+ cells102; LTBMC-IC cells did not expand under these conditions.103 Ex vivo expanded populations of cells have been reinfused into patients following myelosuppressive chemotherapy.104 Because these were autologous transplants in patients who did not receive myeloablative chemotherapy, the contribution of the infused stem cells to long-term hematopoiesis could not be stringently assessed,104 and it is not clear that the infusion of these cells accelerated hematopoietic reconstitution. Other SCF-containing combinations of cytokines are also effective in amplifying the number of BFU-E, CFU-GM, and CFU-GEMM generated in liquid culture.105-108 

SCF synergizes with other cytokines (including Epo, IL-3, GM-CSF, and G-CSF ) to support the direct colony growth of BFU-E, CFU-GM, and CFU-GEMM in semisolid media.98,109-114 Although SCF alone has modest effect on colony growth, in the presence of other cytokines SCF increases both the size and the number of colonies. The combinations of SCF plus IL-9 or SCF plus IL-7 have also been reported to synergistically promote BFU-E or CFU-GM colony growth, respectively.115,116 SCF can also promote progenitor cell survival.117 SCF is required for BFU-E growth under serum-free conditions,118 and CD34+ hematopoietic cells cultured in the presence of SCF plus IL-3 can generate CFU-E,119 suggesting that the deficiency of CFU-E numbers in the marrow or fetal liver of Sl or W mutant mice120 may be due to lack of SCF synergistic activity.119,121,122 Interaction between the c-kit and Epo receptors123 may be essential to enable CFU-E to proliferate and differentiate in response to Epo.124 The combination of SCF, IL-6, and soluble IL-6 receptor can support the proliferation, differentiation, and terminal maturation of BFU-E in vitro, even in the absence of Epo.125 Reports that SCF can reactivate fetal hemoglobin synthesis in BFU-E colonies126 and can retard differentiation of CFU-E in vitro127 may reflect the potent synergistic effect of SCF on the proliferation of less mature erythroid progenitor cells. BFU-E, CFU-GM, and CFU-GEMM can migrate along an SCF gradient, suggesting that SCF can also function as a chemotactic and chemokinetic factor for progenitor cells.128 

Mice with mutations at the Sl and W loci have normal platelet counts,6 indicating that full SCF bioactivity is not an absolute requirement for platelet production in vivo. SCF alone is not a potent stimulant of colony-forming unit-megakaryocyte (CFU-Meg) proliferation or of megakaryocyte nuclear endoreduplication or cytoplasmic maturation in vitro.129-132 However, SCF can synergistically enhance the ability of other cytokines such as Tpo, IL-3, and GM-CSF to promote CFU-Meg colony growth and to increase the size of CFU-Meg colonies.129,130 The addition of SCF to IL-3 doubled the number of CFU-Meg generated in human long-term bone marrow cultures over a 3-month period, indicating the SCF can act on a more primitive population of cells capable of producing CFU-Meg.130 SCF also promotes the growth but not the differentiation of human megakaryocytic cell lines in vitro.131 Thus, SCF predominantly exhibits synergistic proliferative effects on megakaryocytic progenitor cells, especially in combination with Tpo or IL-3.129,130,132 SCF can also potentiate the ability of epinephrine and ADP to induce the secondary wave of platelet aggregation and serotonin secretion.133 

SCF AND MAST CELLS

The profound mast cell deficiency in W/Wv and Sl/Sld mice suggested that SCF may be required for mast cell production. Although the tissues of W/Wv or Sl/Sld mice contain less than 1% of the normal levels of mast cells,134,135 mast cell progenitors are found in the marrow of these mice,136,137 and treatment of Sl/Sld mice with SCF increases the number of mast cells in the skin.4 SCF promotes the survival, proliferation, and maturation of mast cells in vitro138,139 (Table 1). The earliest committed mast cell progenitor, the pro-mastocyte, proliferates and differentiates in vitro in the presence of SCF plus IL-3.140 Mast cells can be cultured from human bone marrow CD34+ cells,141 peripheral blood mononuclear cells,142 cord blood cells,143 or fetal liver cells,144 or from rodent marrow cells145 in the presence of SCF. Optimal murine mast cell proliferation and differentiation in response to SCF may require cofactors such as IL-3, IL-4, or IL-10.146 In cultures maintained in SCF for more than 3 months, mast cell production may predominate over granulocyte-macrophage production.143 

Table 1.

Effects of SCF on Mast Cells

 
In vitro Survival 
 Proliferation 
 Maturation 
 Mediator release 
 Chemotaxis 
 Adhesion to fibroblasts or extracellular matrix 
In vivo Survival 
 Proliferation 
Locally at injection site 
Systemically 
Mediator release 
Histamine 
α Tryptase 
Migration of mast cell precursors 
 
In vitro Survival 
 Proliferation 
 Maturation 
 Mediator release 
 Chemotaxis 
 Adhesion to fibroblasts or extracellular matrix 
In vivo Survival 
 Proliferation 
Locally at injection site 
Systemically 
Mediator release 
Histamine 
α Tryptase 
Migration of mast cell precursors 

SCF also promotes mast cell secretory function,147,148 chemotaxis,149 and adhesion150 and can enhance secretion of mediators in response to IgE-dependent activation148,151 (Table 1). At concentrations similar to that found in normal human serum, SCF stimulates histamine and prostaglandin D2 release from cultured human cutaneous mast cells.148 However, brief preincubation of mast cells with substantially lower concentrations of SCF can potentiate IgE-dependent cutaneous mast cell mediator release.147,148 At concentrations 10- to 100-fold lower than required to stimulate mast cell proliferation, SCF enhances histamine and leukotriene C4 release from human lung mast cells in response to IgE receptor cross-linking.151 SCF can also potentiate IgE-dependent histamine released by human basophils, although basophils appear to be much less sensitive to SCF than are mast cells.148 In murine mast cells, SCF can induce secretion of cytokines (including IL-6 and, to a lesser extent, TNF-α) at concentrations that induce little or no release of preformed mediators such as histamine.152 Mast cell chemotaxis in the direction of a gradient of SCF has also been reported.149 The effects of SCF on mast cell adhesion to fibronectin or to fibroblasts are described in a subsequent section.

In preclinical studies, SCF treatment increased tissue mast cell numbers by greater than 100-fold153,154 and induced mast cell activation in vivo.147 The studies documenting the effects of SCF on mast cell proliferation, maturation, chemotaxis, and degranulation provide important information that may explain the principal toxicity that has been encountered with the use of SCF in vivo.155 

SCF AND LYMPHOPOIESIS

B lymphopoiesis is relatively normal in mice with mutations at the Sl or the W loci.156,157 B lymphopoiesis was not impaired in mice injected with the ACK2 anti–c-kit receptor antibody,158 although erythroid and myeloid cells were virtually eliminated from the marrow.21 In fact, the number of pro-B cells, pre-B cells, and mature B cells increased twofold to fourfold in the mice treated with the ACK2 antibody.158 Transplantation of W/W fetal liver cells into lymphocyte-deficient RAG-2−/− mice resulted in development of all stages of B cells, demonstrating that signal transduction through the c-kit receptor is not essential for B lymphopoiesis in vivo.159 

The initial stages of B-cell development in vitro (production of pro-B cells and pre-B cells) requires factors produced by stromal cells, whereas the maturation of B lymphocytes does not depend on stromal cells.160 Whether SCF is one of the stromal cell-derived factors that is essential for B lymphopoiesis has been intensely investigated. When individual primitive hematopoietic cells (Sca-1+ Lin cells that retain the potential to differentiate along the lymphoid or the myeloid lineages) were cultured in combinations of cytokines, SCF was effective in maintaining the B-lymphoid potential of these cells.161 However, the combination of flk-2/flt3 ligand plus IL-7 may be more potent that the combination of SCF and IL-7 in this respect.162 The most primitive cells that are committed to the B lineage (pro-B cells) do not proliferate in response to SCF, IL-7, or the combination of these two cytokines.163 Pro-B–cell numbers increase as readily on Sl/Sl stromal cells (that do not produce SCF ) as on S17 stromal cells (that do produce SCF ), demonstrating that the growth of the pro-B cells depends on stromal cell factors distinct from SCF.163 The differentiation of pro-B cells to pre-B cells also depends on stromal cell factors other than SCF.164 SCF and IL-7 synergistically stimulate the proliferation of pre-B cells, but SCF is not required for the differentiation of pre-B cells to surface Ig+ B lymphocytes.164,165 Likewise, the proliferative response of B lymphocytes to mitogens does not require SCF/c-kit receptor interaction.165 These reports suggest that SCF exerts its predominant effect on B lymphopoiesis in vitro by enhancing the proliferative response of pre-B cells to IL-7.19 

SCF plays a role in the early stages of T lymphocyte development in vivo.166 The size of the most immature thymocyte compartment in neonatal W/W mice is 1/40 of that found in littermate control mice,166 and W/W fetal liver cells do not contribute to thymopoiesis after transplantation into RAG-2−/− mice.159 Populations of normal CD4 CD8 CD3 thymocytes can proliferate in vitro in response to the combination of SCF plus IL-7.44,167 The ability of CD4 CD8 CD3 thymocytes to reconstitute T-cell differentiation in explants of thymic tissue was ablated by the presence of the ACK2 anti–c-kit receptor antibody,167 suggesting that SCF is critical for early T-lymphocyte development in this in vitro model. Likewise, Sl/Sl fetal thymic tissue, when implanted into a normal host, did not support production of CD4CD8CD3 thymocytes as effectively as did normal fetal thymic tissue implants,166 implying that SCF presentation by the thymic microenvironment is important. The development of intestinal intraepithelial lymphocyte populations is dysregulated in W/Wv and Sl/Sld mice,168 suggesting that SCF/c-kit receptor interaction is important for normal function of the intestinal immune system. SCF may also affect mature T-cell function by potentiating the allogeneic mixed lymphocyte reaction.169 

Natural killer (NK) cells are a subset of large granular lymphocytes that are important for the immune response to viral infection and tumor cells. CD34+ human hematopoietic cells can differentiate into NK cells in vitro in the presence of SCF plus IL-2.170 SCF also enhances the ability of CD56bright NK cells to proliferate in response to IL-2.171 However, exposure to SCF did not increase the cytotoxicity of the CD56bright NK cells against K562 cells (NK activity) or augment IL-2–induced LAK activity.171 

Dendritic cells are efficient antigen-presenting cells that play a role in T-cell immunity. When CD34+ human marrow cells were cultured in GM-CSF plus TNF-α, the addition of SCF increased the number of dendritic cell progenitors generated up to 100-fold, demonstrating that SCF can amplify dendritic cell progenitor numbers in vitro.172 SCF also synergized with GM-CSF and TNF-α to directly increase the number of dendritic cells produced from CD34+ human marrow cells; the dendritic cells thus generated were capable of stimulating resting T cells in the allogeneic mixed leukocyte reaction.172,173 

SCF AND ADHESION

Hematopoiesis occurs in close proximity to bone marrow stromal cells and to extracellular matrix molecules such as fibronectin.174 A number of adhesive interactions maintain the intimate association of hematopoietic stem cells and progenitor cells and marrow stromal elements. Normal hematopoietic progenitor cells express the integrins VLA-4 and VLA-5175 and can adhere in vitro to stromal cells that display VCAM-1176 or to specific sites on fibronectin.177,178 Adhesion to fibronectin declines with terminal erythroid differentiation179 and may modulate progenitor cell proliferation.180 Other adhesive interactions may also be important.174,181 

Evidence that SCF can modulate the adhesive behavior of hematopoietic cells is derived from studies of mast cells,14,150,182-185 of hematopoietic cell lines,186,187 and of normal hematopoietic cells.187,188 Exposure to SCF increases adherence of CD34+ marrow cells to fibronectin,187 and hematopoietic progenitor cells from W/Wv mice exhibit diminished basal adhesion to stromal cells.189 Stimulation of mast cell adhesion to fibronectin requires 10- to 100-fold less SCF than does stimulation of mast cell proliferation in vitro.182,185 SCF treatment initially increases (over 30 to 60 minutes) and then decreases (over 24 hours) adhesion of hematopoietic cell lines to VCAM-1 or to fibronectin.186 These effects were mediated not by a change in the number of VLA-4 or VLA-5 molecules displayed on the hematopoietic cell surface, but by an alteration in their avidity for VCAM-1 or fibronectin. Other cytokines can also modulate VLA-4 and VLA-5 adhesive function.187 Several of these reports document that SCF-induced cellular adhesion requires c-kit receptor kinase activity. These results suggest that the mechanism of SCF-induced progenitor cell adhesion to VCAM-1 or fibronectin may involve alteration of integrin avidity. An alternative possibility is that the transmembrane form of SCF displayed on fibroblasts binds directly to the c-kit receptor on the surface of hematopoietic cells and thus helps to anchor the hematopoietic cells in the microenvironment.14,183,190 The report that mast cells derived from W/W42 mice (that display the c-kit receptor protein on the cell surface but lack c-kit receptor kinase activity) can adhere normally to fibroblasts184 provides support for the latter model. However, the preponderance of data argues that SCF binding to the c-kit receptor and activation of c-kit receptor kinase activity results in an inside-out signal that modulates integrin avidity on the surface of hematopoietic cells, thereby altering integrin adhesive function.186-188 

Because of the strong correlation between the ability of cytokines to induce hematopoietic progenitor cells to proliferate and to adhere to fibronectin, it has been proposed that the cytokine-induced inside-out signal that alters integrin avidity on the hematopoietic cell surface may be followed by an outside-in signal transmitted via the integrins that may promote cell proliferation in cooperation with the hematopoietic growth factors.188 Likewise, SCF-induced enhancement of integrin avidity for fibronectin may potentiate phosphorylation of the focal adhesion kinase pp125FAK,191 which plays a key role in integrin-mediated signalling.

Normal human endothelial cells display high-affinity c-kit receptors,40 and it is possible that SCF binding to endothelial cells or to other marrow stromal cells could alter the adhesive phenotype of these cells. Stimulation of endothelial cells with SCF in vitro did not induce display of the adhesion molecules VCAM-1, ELAM-1, or ICAM-1.40 A preliminary report indicates that SCF treatment of a marrow stromal cell line induced the expression of hemonectin, which could potentially mediate adhesion of progenitor cells.192,193 Expression of human c-kit cDNA in porcine aortic endothelial cells conferred the ability to proliferate, to undergo cytoskeletal reorganization, and to migrate in response to human SCF,194 demonstrating that these cells have the capacity to respond to SCF. The potential effects of SCF on the adhesive function of marrow stromal cells has not been fully explored.

SCF AND HEMATOPOIETIC STEM CELL/PROGENITOR CELL MOBILIZATION

The mechanisms that govern the trafficking of hematopoietic stem cells and progenitor cells between the bone marrow and blood in vivo are not understood in detail. Injection of mice with SCF results in a profound redistribution of primitive hematopoietic cells from the bone marrow into the blood and spleen.195,196 Primates treated with SCF demonstrate a 10- to 100-fold increase in the number of circulating progenitor cells and mobilization of cells that engraft lethally irradiated recipients.197,198 Treatment of primates or mice with antibodies against the integrin VLA-4 or against its counter receptor VCAM-1 also results in egress of progenitor cells from the marrow into the blood,199,200 suggesting that interaction of VLA-4 expressed on hematopoietic cells and VCAM-1 constitutively displayed by microenvironmental cells may play a role in the trafficking of primitive hematopoietic cells in vivo. It is possible that SCF-induced mobilization of stem cells and progenitor cells from the bone marrow into the blood may be mediated in part by alterations in the interactions of hematopoietic cell integrins with VCAM-1 or fibronectin, but multiple mechanisms are likely to be involved.201 

Phase I clinical studies showed that treatment with SCF increases the numbers of progenitor cells of many types (including BFU-E, CFU-GM, CFU-Meg, and CFU-GEMM) in the marrow.202 A randomized clinical trial in patients with ovarian cancer compared the ability of SCF plus G-CSF with that of G-CSF alone to mobilize LTBMC-IC203; all patients also received cyclophosphamide. Treatment with SCF resulted in a fivefold to sixfold increase in the number of LTBMC-IC mobilized, as well as an increase in the total number of CD34+ cells mobilized.203 

Preclinical studies in mice showed that SCF treatment can expand the total number of stem cells capable of lymphohematopoietic reconstitution, as well as the numbers of CFU-S and direct colony-forming cells.204-207 Hematopoietic cells obtained from mice previously treated with SCF or with SCF plus G-CSF were shown to be excellent targets for retrovirally mediated gene transfer206,208; these studies have recently been extended to primates.209 The combination of SCF plus G-CSF synergistically increased the number of CFU-S in the blood and increased the short-term and long-term repopulating ability of the circulating murine hematopoietic cells.196,205,210 The murine hematopoietic cells mobilized by SCF plus G-CSF maintained marrow repopulating ability on serial transplantation, whereas the hematopoietic cells mobilized by G-CSF had poor repopulating function on secondary transplantation.210 Thus, the population of cell mobilized by SCF plus G-CSF is functionally different than that mobilized by G-CSF alone. Autologous peripheral blood stem cell transplant studies in baboons showed that the use of cells mobilized with SCF plus G-CSF significantly accelerated neutrophil and platelet recovery in comparison to the use of cells mobilized with G-CSF alone.211 Whether the results of these preclinical studies will translate into clinical benefit in human peripheral blood stem cell transplantation remains to be seen.

SCF AND RADIATION

Treatment with SCF alters sensitivity to radiation therapy. The increased radiosensitivity of mice with Sl and W mutations has long been known212 and may be due to the ability of SCF to suppress apoptosis and promote cell cycle progression.213 Mice receiving SCF at specific times before radiation therapy were protected from radiation-induced death, possibly because SCF promotes hematopoietic cell entry into the relatively radioresistant S phase of the cell cycle.214 Pretreatment with SCF also increases the survival of murine duodenal crypt stem cells, which may decrease radiation-induced gut toxicity.215 Mice receiving SCF after radiation therapy demonstrated accelerated recovery of white blood cell and platelet counts.216 Treatment of dogs with SCF after radiation therapy permitted survival despite otherwise lethal doses of radiation.217 Conversely, neutralization of SCF activity increased sensitivity to radiation-induced death.218 SCF as a single agent has generally not accelerated hematopoietic recovery when administered after myelosuppressive chemotherapy or stem cell/progenitor cell transplantation,219-221 although the combination of SCF plus IL-11 may enhance neutrophil and platelet recovery.220 

DIFFERENTIAL EFFECTS OF SOLUBLE AND TRANSMEMBRANE SCF

The soluble and transmembrane forms of SCF display somewhat different effects in vitro. Transmembrane SCF expressed by a fibroblast cell line was able to support hematopoiesis (production of CFU-GM) for a several week longer period of time than was soluble SCF produced by the fibroblast cell line.34 Transmembrane SCF is a more potent stimulant of primordial germ cell survival in vitro than is soluble SCF222,223 and may also mediate binding of germ cells to Sertoli cells in the testis.36 Soluble SCF appears to activate the c-kit receptor more transiently and to induce more rapid downregulation of cell surface c-kit receptor display than does transmembrane SCF.224 The duration of activation of the MAP kinase pathway can influence the cellular response (proliferation v differentiation) to the signal in a neuronal cell line225; it is possible that this concept could apply to signaling via the c-kit receptor as well. However, the basis for the differing effects of soluble and transmembrane SCF is not fully understood at present.

Fig. 3.

The c-kit receptor. The ATP binding site is found in the kinase domain proximal to the cell membrane. The phosphotransferase region is in the kinase domain distal to the cell membrane. As described in the text, a soluble form of the c-kit receptor generated by cleavage at a site near the membrane-spanning region has also been identified.

Fig. 3.

The c-kit receptor. The ATP binding site is found in the kinase domain proximal to the cell membrane. The phosphotransferase region is in the kinase domain distal to the cell membrane. As described in the text, a soluble form of the c-kit receptor generated by cleavage at a site near the membrane-spanning region has also been identified.

The phenotypes of Sl/Sld mice6,14,15 and of male Sl/Sl17H mice73 suggest that the presence of soluble SCF cannot fully overcome the lack of normally expressed transmembrane SCF. The Sld mutation may also diminish the quantity of soluble SCF produced; SCF activity was not detected in the supernatant of fibroblasts from Sl/Sld mice,137 and administration of exogenous SCF to Sl/Sld mice increased mast cell numbers and hematocrit.4 Despite the low binding affinity of soluble human SCF for the murine c-kit receptor,71 transgenic expression of the transmembrane form of human SCF in mice resulted in abnormalities of coat color reminiscent of certain W alleles,226 suggesting that the human transmembrane SCF blocked the ability of native murine SCF to activate the c-kit receptor in melanocytes.

Transgenic expression of an obligate transmembrane form of murine SCF in Sl/Sld mice dramatically expanded erythropoiesis, but had little effect on myelopoiesis. In contrast, enforced expression of soluble murine SCF in the Sl/Sld mice increased myelopoiesis but not erythropoiesis.227 These results suggest that the presentation of SCF, whether in a transmembrane form by marrow microenvironmental cells or in a soluble form, may differentially influence the proliferation of erythroid and myeloid progenitor cells. As previously discussed, the transmembrane form of SCF may guide the migration of hematopoietic cells, germ cells, and melanocytes to their final destinations during embryogenesis17,18 or may be required for melanocyte survival in the skin.228 

THE c-kit RECEPTOR

The c-kit receptor229 is a member of the type III receptor tyrosine kinase family67,68 (reviewed in Ullrich and Schlessinger230 ). This family of cytokine receptors also encompasses the c-fms receptor, the platelet-derived growth factor (PDGF ) receptors, and flk-2/flt3 receptor. The structure of these receptors includes an extracellular domain with five Ig-like motifs, a single short membrane-spanning domain, and a cytoplasmic domain with tyrosine kinase activity (Fig 3). The kinase domain is interrupted by a kinase insert sequence that divides the kinase domain into an ATP binding region and phosphotransferase region. The c-kit receptor is a 145,000-dalton glycoprotein67 and has been given the designation CD117. Binding of SCF (which circulates as a noncovalently associated dimer)58 triggers c-kit receptor homodimerization and intermolecular tyrosine phosphorylation of the receptor, creating docking sites for a number of SH2-containing signal transduction molecules.231 The signal transduction pathways employed by the c-kit receptor will not be covered in this review. An elegant genetic analysis suggests that a protein tyrosine phosphatase, SHP1, may terminate c-kit receptor signal transduction by modulating phosphorylation of downstream substrates of the c-kit receptor.232,233 

Deletion analysis and construction of chimeric human-mouse c-kit receptors have suggested that the three amino-terminal Ig-like domains of the c-kit receptor contain the SCF binding site and that the fourth Ig-like domain may contain a site required for c-kit receptor dimerization.234-236 A recombinant soluble form of the c-kit receptor, truncated at the juncture of the extracellular and transmembrane domains, can bind SCF and undergo ligand-induced dimerization,237-239 demonstrating that all of the structural information required for these processes is present in the extracellular domain of the receptor.

Alternative splicing results in two naturally occurring isoforms of the c-kit receptor that contain (designated kit A) or lack (designated kit) four amino acids (Gly Asn Asn Lys) at codon 510 just outside the transmembrane domain.240 These two c-kit receptor isoforms coexist in normal tissues. The ratio of kit A to kit mRNA in normal human bone marrow is approximately 1:5.241 In marrow from patients with acute myelogenous leukemia, the ratio varies considerably, but there is no association with French-American-British subtype or clinical outcome.241 The biologic significance of these two isoforms of the c-kit receptor remains unclear.

Point mutations in the c-kit receptor cytoplasmic domain have been identified in murine and human mast cell lines and in hematopoietic cells from patients with mast cell disorders. Mutation of Asp814 in the kinase domain in a murine mast cell line and mutation of the corresponding amino acid (Asp816 ) in a human mast cell line confer factor-independent growth, constitutive tyrosine phosphorylation of the c-kit receptor, mast cell differentiation, and tumorigenicity in vivo.242-246 The Asp816 mutation has also been found in peripheral blood mononuclear cells from patients with mastocytosis and an associated myelodysplastic disorder247 and in mast cells from patients with urticaria pigmentosa.248 Mutation of Asp814 alters the substrate specificity of the c-kit receptor and results in ubiquitinization and accelerated degradation of SHP1,249 the tyrosine phosphatase that normally attenuates c-kit receptor signal transduction. A mutation of Val559 in the juxtamembrane region of the c-kit receptor, which has been identified in a human mast cell line, results in ligand-independent dimerization and constitutive activation of the c-kit receptor.250 Deletion of seven amino acids (Thr573-His579 ) in the juxtamembrane domain likewise resulted in constitutive activation of the c-kit receptor in a murine mast cell line.251 Thus, structural and functional characterization of the c-kit receptor in mast cell lines or in cells from mastocytosis patients has identified single amino acid mutations and a short deletion in the cytoplasmic domain of the c-kit receptor that can be associated with neoplastic transformation of mast cells.

Mutations in the c-kit receptor have also been found in patients with the autosomal dominant disorder piebaldism.252-255 Human piebaldism is characterized by a white hair forelock and hypopigmented patches on the trunk and extremities, reminiscent of the murine W (dominant white spotting) mutation. The hypopigmented areas of skin in individuals with piebaldism are devoid of melanocytes, possible due to failure of melanocyte migration during embryogenesis. Unlike the murine W mutation, anemia and infertility are not features of human piebaldism.

CELLULAR DISTRIBUTION OF THE c-kit RECEPTOR

The c-kit receptor is broadly distributed within the hierarchy of hematopoietic cells and is also found in other tissues.25,40,47,120 Cell populations enriched for murine hematopoietic stem cells, defined by the ability to reconstitute donor-derived lymphohematopoiesis in lethally irradiated hosts for more than 6 months, display the c-kit receptor on the cell surface.256 A study in which primitive murine hematopoietic cells were separated into c-kit receptor<low and c-kit receptorlow populations and then transplanted into lethally irradiated recipients showed that both populations of cells could reconstitute lymphohematopoiesis in the primary recipients for at least 6 months.257 A report using a different transplant model (human hematopoietic cells transplanted into fetal sheep) showed that the CD34+c-kitlow population of cells contained the long-term reconstituting activity.258 However, most reports,256,258-260 although not all reports,261 agree that c-kit receptor purified populations of hematopoietic cells lack long-term reconstituting activity. Injection of a single murine hematopoietic cell with the phenotype CD34low/−, c-kit receptor+, Sca-1+, Lin was capable of reconstituting lymphohematopoiesis for more than 6 months in a portion of recipient mice,262 and donor-derived cells from recipient mice could repopulate lethally irradiated secondary recipients, convincingly demonstrating that the true lymphohematopoietic stem cell with extensive self-renewal capacity displays the c-kit receptor.262,263 

The cells that confer radioprotection when transplanted into irradiated recipients, also known as short-term repopulating cells, are also c-kit receptor+,260 as are CFU-S. In populations of human CD34+ hematopoietic cells, approximately 60% to 75% of the cells coexpress the c-kit receptor.264,265 Thus, there is substantial but not complete overlap between the cellular distribution of the CD34 antigen and the c-kit receptor on hematopoietic cells.

Hematopoietic progenitor cells exhibit the c-kit receptor. When c-kit receptor+ hematopoietic cells are selected using a monoclonal antibody and cultured in direct colony-forming assays, the c-kit receptor+ population of cells is greatly enriched in BFU-E, CFU-GM, CFU-Meg, CFU-GEMM, LTBMC-IC, and CFU-E, whereas the c-kit receptor population of cells is depleted of colony-forming cells.21,256,264-267 Cell sorting experiments based on detection of biotinylated SCF binding to marrow cells suggested that the density of c-kit receptor display on BFU-E is higher than on CFU-GM or on CFU-E.268 However, experiments using an anti–c-kit receptor monoclonal antibody showed similar density of c-kit receptor display on BFU-E, CFU-GM, and CFU-GEMM.269 The latter result suggests that the profound effect of SCF on erythropoiesis in vivo and in vitro, in comparison to its effects on myelopoiesis, is not due to differential receptor density at the progenitor cell level. The c-kit receptor can physically associate with the cytoplasmic domain of the Epo receptor in cells responsive to both cytokines; this observation may provide a molecular explanation for the potent synergistic effects of SCF and Epo on erythropoiesis.123 

Recognizable hematopoietic precursor cells also exhibit c-kit receptor on the cell surface. Autoradiographic analysis of 125I-SCF binding to human or murine marrow cells demonstrates a plenitude of grains associated with recognizable erythroblasts, myeloblasts, and megakaryocytes (Fig 4) and a decrease in grain density in parallel to maturation.114,265 Mast cells also exhibit c-kit receptors.270 Platelets display the c-kit receptor after activation with ADP; resting platelets are devoid of cell surface c-kit receptors.133 

The c-kit receptor is found on normal B- and T-lymphocyte progenitor cells as well.19 Approximately 85% of pro-B cells display the c-kit receptor.163 A portion of pre-B cells also exhibit the c-kit receptor at low density; c-kit expression is lost as these cells mature to surface Ig+ B lymphocytes.158,165 Of CD4 CD8 CD3 thymocytes, approximately 30% exhibit the c-kit receptor.44 As is true for B-lymphocyte progenitor cells, c-kit receptor density is highest on the least mature subpopulation of the CD4 CD8 CD3 thymocytes.167 These reports provide insights into c-kit receptor display during differentiation and maturation of normal hematopoietic cells and suggest a model in which the c-kit receptor is found at low density on primitive hematopoietic cells capable of long-term lymphohematopoietic reconstitution, increases in density to reach a peak at the progenitor cell level, and then decreases with terminal maturation of hematopoietic precursor cells.271 

Neoplastic human hematopoietic cells can also display the c-kit receptor. Virtually all patients presenting with acute myelogenous leukemia have c-kit receptor+ blasts, and SCF can stimulate the proliferation of these cells.272-274 In contrast, leukemic blasts from patients with acute lymphocytic leukemia rarely display the c-kit receptor.272,275 Most non-Hodgkin's lymphomas lack c-kit receptor expression,40,276,277 with the exception of anaplastic large-cell lymphomas that can display the c-kit receptor.276 Lymph nodes from patients with Hodgkin's disease also express the c-kit receptor.276 The c-kit receptor is ubiquitously found on human hematopoietic cell lines of the erythroid and megakaryocytic phenotypes and on some myeloid and lymphoid cell lines as well.131,265,278 Receptor density is highest in erythroleukemia cell lines, which may express up to 50,000 to 100,000 c-kit receptors per cell.238 The majority of cell lines studied display a single class of high-affinity (kd of 50 to 200 pmol/L) binding sites; this is similar to the binding affinity found on normal human hematopoietic cells.279 A number of human solid tumor cell lines (including small cell lung cancer, breast cancer, and neuroblastoma) as well as a variety of fresh human tumor tissues (particularly small cell lung cancer, testicular seminoma, glioblastoma, and some breast cancer samples) have been shown to display the c-kit receptor protein.280-284 

MODULATION OF c-kit RECEPTOR EXPRESSION

Display of the c-kit receptor on hematopoietic cells is modulated in a number of ways. Binding of SCF induces rapid internalization of the SCF–c-kit–receptor complex (see cover figure),270,285,286 likely via clathrin-coated pits.287 In parallel, the c-kit receptor is ubiquitinated and targeted for degradation by the proteasome proteolytic pathway.285,286 Internalization and ubiquitination of the c-kit receptor requires the tyrosine kinase activity of the c-kit receptor, but not association and activation of PI 3′ kinase.286 Treatment of cells with chloroquine partially blocks c-kit receptor degradation, suggesting that lysosomal proteases may also be involved.285 Whether a portion of the internalized c-kit receptors is parsimoniously recycled to the cell surface for reuse is unclear at present. Exposure of hematopoietic cells to TGF-β, TNF-α, or IL-4 can downregulate cell surface c-kit receptor display by transcriptional or posttranscriptional mechanisms.288-291 As described below, the c-kit receptor can also be proteolytically cleaved in the juxtamembrane region and shed from the cell surface40,238,270,292; this process can be accelerated by activators of protein kinase C.

SOLUBLE c-kit RECEPTOR

A number of cell surface cytokine receptors have soluble counterparts that are generated by alternative mRNA splicing or by proteolytic cleavage of the cell surface form of the receptor.293,294 Many soluble receptors function as natural antagonists by competing with the cell surface receptor for cytokine binding. Soluble receptors may also function as carriers for the ligand to prolong ligand half-life in vivo,295 may mediate cytokine binding to transmembrane signal transduction subunits of the receptor,296 or may potentiate signal transduction via transmembrane receptor subunits even in the absence of the ligand by as yet unidentified mechanisms.297 Decreased cytokine receptor density on the cell surface is one mechanism that can attenuate cellular response to the cytokine.298 Whether soluble cytokine receptors normally serve to modulate ligand bioactivity in vivo or whether they are a byproduct of cellular desensitization to the ligand remains unclear at present.

Soluble c-kit receptor is released by human hematopoietic cells, mast cells, and endothelial cells40,238,270,292 and circulates in normal human plasma at a concentration of approximately 325 ng/mL.299 The quantity of soluble c-kit receptor in the plasma exceeds that of SCF by a 30-fold molar ratio. Native soluble human c-kit receptor binds SCF with an affinity comparable to that of the cell surface form of the receptor.238 Recombinant soluble c-kit receptor can bind SCF and can antagonize SCF-induced tyrosine phosphorylation of the cell surface c-kit receptor in vitro.237 A form of recombinant soluble murine c-kit receptor, fused to the Fc domain of human IgG and thus an obligate dimer, binds murine SCF with high affinity (kd of 300 pmol/L) and blocks SCF-induced cell proliferation in vitro.300 The stoichiometry of interaction of SCF and recombinant soluble c-kit receptor is 2:2.239 These reports suggest that the quantity and binding affinity of the soluble c-kit receptor present in vivo are sufficient to modulate SCF bioactivity, although this has not been directly demonstrated.

POTENTIAL CLINICAL USES FOR SCF

The potential cornucopia of clinical uses for SCF has been limited by the adverse events encountered in initial clinical trials.155,203 Dermal mast cell degranulation resulting in a pruritic wheal with surrounding edema at the SCF injection site occurs in most patients and resolves within 24 hours.155,203 Melanocyte proliferation and increased melanization of the epidermis, resulting in 3- to 5-cm diameter areas of increased skin pigmentation at SCF injection sites, has been reported in some patients receiving SCF at 5 to 50 μg/kg/d for 14 days.155,301 The hyperpigmentation generally resolves after 2 to 12 months. Approximately 10% to 20% of the patients in two studies developed an allergic-like reaction characterized by urticaria, with or without respiratory symptoms suggestive of laryngeal edema, that required discontinuation of SCF treatment.155,203 The effects of SCF on mast cells appear to be dose-dependent,155 and it is possible that the potent synergistic effects of SCF noted in vitro could be exploited in vivo. For example, low doses of SCF could be used in conjunction with G-CSF or other cytokines as a stem cell and progenitor cell mobilizing agent; clinical trials of SCF plus G-CSF are currently underway.203,302,303 The latter studies have shown an improved safety profile for SCF when used at lower doses. The incidence of allergic-like reactions was approximately 2% in 400 SCF-treated patients.303 Analogs of SCF with enhanced ability to stimulate the proliferation and modulate the adhesive function of hematopoietic cells yet no increased effect on mast cell activation have been designed304,305 and are currently in preclinical trials (K. Nocka, personal communication, November 1996). Hematopoietic cells exposed to SCF either in vivo206,208,209 or in vitro306 are more efficiently transduced by retroviral vectors; this may prove useful for gene therapy. Ex vivo expansion of hematopoietic stem cells and progenitor cells is another potential use for SCF; many of the cytokine cocktails used for this purpose contain SCF.104 Although the number of progenitor cells can be expanded many fold, whether the number of stem cells can actually be increased ex vivo with presently available techniques remains an area of debate.307,308 

Therapeutic approaches based on the c-kit receptor protein may eventually have clinical utility. Because the c-kit receptor is displayed on the surface of hematopoietic stem cells and progenitor cells, selection of these cells by immunoaffinity techniques (similar to those currently in clinical use to select hematopoietic cells expressing the CD34 antigen) may provide a population of cells useful for gene targeting and for transplantation.309 The recent success of retrovirally mediated gene transfer by targeting the erythropoietin receptor310 and the use of an adenoviral vector linked to SCF to target cells expressing the c-kit receptor311 underscore the potential of this approach.

NOTE ADDED IN PROOF

Recent results suggest that SCF may be predominantly monomeric at the concentration found in human serum312 and that the fourth Ig-like domain of the receptor is not required for SCF-induced c-kit receptor dimerization.313 

ACKNOWLEDGMENT

The author thanks Drs Andrew Bohm and Kenneth Kaushansky for their assistance with Fig 2 and Drs Robert Andrews, George Demetri, Stephen Galli, Keith Langley, Karl Nocka, Thalia Papayannopoulou, and David Williams for helpful discussions and/or providing access to unpublished information.

Supported by National Institutes of Health Grant No. DK44194 and by an American Cancer Society Faculty Research Award.

Address reprint requests to Virginia C. Broudy, MD, Division of Hematology, University of Washington, Box 357710, Seattle, WA 98195-7710.

REFERENCES

REFERENCES
1
Metcalf
D
Hematopoietic regulators: Redundancy or subtlety?
Blood
82
1993
3515
2
Williams
DE
Eisenman
J
Baird
A
Rauch
C
Ness
KV
March
CJ
Park
LS
Martin
U
Mochizuki
DY
Boswell
HS
Burgess
GS
Cosman
D
Lyman
SD
Identification of a ligand for the c-kit proto-oncogene.
Cell
63
1990
167
3
Flanagan
JG
Leder
P
The kit ligand: A cell surface molecule altered in steel mutant fibroblasts.
Cell
63
1990
185
4
Zsebo
KM
Williams
DA
Geissler
EN
Broudy
VC
Martin
FH
Atkins
HL
Hsu
R-Y
Birkett
NC
Okino
KH
Murdock
DC
Jacobsen
FW
Langley
KE
Smith
KA
Takeishi
T
Cattanach
BM
Galli
SJ
Suggs
SV
Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor.
Cell
63
1990
213
5
Huang
E
Nocka
K
Beier
DR
Chu
T-Y
Buck
J
Lahm
H-W
Wellner
D
Leder
P
Besmer
P
The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus.
Cell
63
1990
225
6
Russell
ES
Hereditary anemias of the mouse: A review for geneticists.
Adv Genet
20
1979
357
7
Geissler
EN
McFarland
EC
Russell
ES
Analysis of pleiotropism at the dominant white-spotting (W) locus of the house mouse: A description of ten new W alleles.
Genetics
97
1981
337
8
Besmer P, Manova K, Duttlinger R, Huang EJ, Packer A, Gyssler C, Bachvarova RF: The kit-ligand (steel factor) and its receptor c-kit/W: Pleiotropic roles in gametogenesis and melanogenesis. Development 125, 1993 (suppl)
9
Tan
JC
Nocka
K
Ray
P
Traktman
P
Besmer
P
The dominant W42 spotting phenotype results from a missense mutation in the c-kit receptor kinase.
Science
247
1990
209
10
Blouin R, Bernstein A: The white spotting and steel hereditary anemias of the mouse, in Feig SA, Freedman MH (eds): Clinical Disorders and Experimental Models of Erythropoietic Failure. Boca Raton, FL, CRC, 1993, p 157
11
Huizinga
JD
Thuneberg
L
Klüppel
M
Malysz
J
Mikkelsen
HB
Bernstein
A
W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity.
Nature
373
1995
347
12
Maeda
H
Yamagata
A
Nishikawa
S
Yoshinaga
K
Kobayashi
S
Nishi
K
Nishikawa
S-I
Requirement of c-kit for development of intestinal pacemaker system.
Development
116
1992
369
13
Reith
AD
Rottapel
R
Giddens
E
Brady
C
Forrester
L
Bernstein
A
W mutant mice with mild or severe developmental defects contain distinct point mutations in the kinase domain of the c-kit receptor.
Genes Dev
4
1990
390
14
Flanagan
JG
Chan
DC
Leder
P
Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the Sld mutant.
Cell
64
1991
1025
15
Brannan
CI
Lyman
SD
Williams
DE
Eisenman
J
Anderson
DM
Cosman
D
Bedell
MA
Jenkins
NA
Copeland
NG
Steel-dickie mutation encodes a c-Kit ligand lacking transmembrane and cytoplasmic domains.
Proc Natl Acad Sci USA
88
1991
4671
16
Orr-Urtreger
A
Avivi
A
Zimmer
Y
Givol
D
Yarden
Y
Lonai
P
Developmental expression of c-kit, a proto-oncogene encoded by the W locus.
Development
109
1990
911
17
Matsui
Y
Zsebo
KM
Hogan
BLM
Embryonic expression of a haematopoietic growth factor encoded by the Sl locus and the ligand for c-kit.
Nature
347
1990
667
18
Keshet
E
Lyman
SD
Williams
DE
Anderson
DM
Jenkins
NA
Copeland
NG
Parada
LF
Embryonic RNA expression patterns of the c-kit receptor and its cognate ligand suggest multiple functional roles in mouse development.
EMBO J
10
1991
2425
19
Palacios
R
Nishikawa
S-I
Developmentally regulated cell surface expression and function of c-kit receptor during lymphocyte ontogeny in the embryo and adult mice.
Development
115
1992
1133
20
Motro
B
Wojtowicz
JM
Bernstein
A
van der Kooy
D
Steel mutant mice are deficient in hippocampal learning but not long-term potentiation.
Proc Natl Acad Sci USA
93
1996
1808
21
Ogawa
M
Matsuzaki
Y
Nishikawa
S
Hayashi
S-I
Kunisada
T
Sudo
T
Kina
T
Nakauchi
H
Nishikawa
S-I
Expression and function of c-kit in hemopoietic progenitor cells.
J Exp Med
174
1991
63
22
Heinrich
MC
Dooley
DC
Freed
AC
Band
L
Hoatlin
ME
Keeble
WW
Peters
ST
Silvey
KV
Ey
FS
Kabat
D
Maziarz
RT
Bagby
GC Jr
Constitutive expression of steel factor gene by human stromal cells.
Blood
82
1993
771
23
Linenberger
ML
Jacobsen
FW
Bennett
LG
Broudy
VC
Martin
FH
Abkowitz
JL
Stem cell factor production by human marrow stromal fibroblasts.
Exp Hematol
23
1995
1104
24
Broudy
VC
Lin
NL
Priestley
GV
Nocka
K
Wolf
NS
Interaction of stem cell factor and its receptor c-kit mediates lodgment and acute expansion of hematopoietic cells in the murine spleen.
Blood
88
1996
75
25
Yoshinaga
K
Nishikawa
S
Ogawa
M
Hayashi
S-I
Kunisada
T
Fujimoto
T
Nishikawa
S-I
Role of c-kit in mouse spermatogenesis: Identification of spermatogonia as a specific site of c-kit expression and function.
Development
113
1991
689
26
Nishikawa
S
Kusakabe
M
Yoshinaga
K
Ogawa
M
Hayashi
S
Kunisada
T
Era
T
Sakakura
T
Nishikawa
S
In utero manipulation of coat color formation by a monoclonal anti-c-kit antibody: Two distinct waves of c-kit-dependency during melanocyte development.
EMBO J
10
1991
2111
27
Donaldson
LE
Schmitt
E
Huntley
JF
Newlands
GFJ
Grencis
RK
A critical role for stem cell factor and c-kit in host protective immunity to an intestinal helminth.
Int Immunol
8
1996
559
28
Copeland
NG
Gilbert
DJ
Cho
BC
Donovan
PJ
Jenkins
NA
Cosman
D
Anderson
D
Lyman
SD
Williams
DE
Mast cell growth factor maps near the steel locus on mouse chromosome 10 and is deleted in a number of steel alleles.
Cell
63
1990
175
29
Anderson
DM
Williams
DE
Tushinski
R
Gimpel
S
Eisenman
J
Cannizzaro
LA
Aronson
M
Croce
CM
Huebner
K
Cosman
D
Lyman
SD
Alternate splicing of mRNAs encoding human mast cell growth factor and localization of the gene to chromosome 12q22-q24.
Cell Growth Differ
2
1991
373
30
Geissler
EN
Liao
M
Brook
JD
Martin
FH
Zsebo
KM
Housman
DE
Galli
SJ
Stem cell factor (SCF ), a novel hematopoietic growth factor and ligand for c-kit tyrosine kinase receptor, maps on human chromosome 12 between 12q14.3 and 12qter.
Somatic Cell Mol Genet
17
1991
207
31
Galli
SJ
Zsebo
KM
Geissler
EN
The kit ligand, stem cell factor.
Adv Immunol
55
1994
1
32
Huang
EJ
Nocka
KH
Buck
J
Besmer
P
Differential expression and processing of two cell associated forms of the kit-ligand: KL-1 and KL-2.
Mol Biol Cell
3
1992
349
33
Anderson
DM
Lyman
SD
Baird
A
Wignall
JM
Eisenman
J
Rauch
C
March
CJ
Boswell
HS
Gimpel
SD
Cosman
D
Williams
DE
Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms.
Cell
63
1990
235
34
Toksoz
D
Zsebo
KM
Smith
KA
Hu
S
Brankow
D
Suggs
SV
Martin
FH
Williams
DA
Support of human hematopoiesis in long-term bone marrow cultures by murine stromal cells selectively expressing the membrane-bound and secreted forms of the human homolog of the steel gene product, stem cell factor.
Proc Natl Acad Sci USA
89
1992
7350
35
Huang
EJ
Manova
K
Packer
AI
Sanchez
S
Bachvarova
RF
Besmer
P
The murine steel panda mutation affects kit ligand expression and growth of early ovarian follicles.
Dev Biol
157
1993
100
36
Marziali
G
Lazzaro
D
Sorrentino
V
Binding of germ cells to mutant Sld Sertoli cells is defective and is rescued by expression of the transmembrane form of the c-kit ligand.
Dev Biol
157
1993
182
37
Majumdar
MK
Feng
L
Medlock
E
Toksoz
D
Williams
DA
Identification and mutation of primary and secondary proteolytic cleavage sites in murine stem cell factor cDNA yields biologically active, cell-associated protein.
J Biol Chem
269
1994
1237
38
Pandiella
A
Bosenberg
MW
Huang
EJ
Besmer
P
Massagué
J
Cleavage of membrane-anchored growth factors involves distinct protease activities regulated through common mechanisms.
J Biol Chem
267
1992
24028
39
Arribas
J
Coodly
L
Vollmer
P
Kishimoto
TK
Rose-John
S
Massagué
J
Diverse cell surface protein ectodomains are shed by a system sensitive to metalloprotease inhibitors.
J Biol Chem
271
1996
11376
40
Broudy
VC
Kovach
NL
Bennett
LG
Lin
N
Jacobsen
FW
Kidd
PG
Human umbilical vein endothelial cells display high-affinity c-kit receptors and produce a soluble form of the c-kit receptor.
Blood
83
1994
2145
41
Longley
BJ Jr
Morganroth
GS
Tyrrell
L
Ding
TG
Anderson
DM
Williams
DE
Halaban
R
Altered metabolism of mast-cell growth factor (c-kit ligand) in cutaneous mastocytosis.
N Engl J Med
328
1993
1302
42
Klimpel
GR
Chopra
AK
Langley
KE
Wypych
J
Annable
CA
Kaiserlian
D
Ernst
PB
Peterson
JW
A role for stem cell factor and c-kit in the murine intestinal tract secretory response to cholera toxin.
J Exp Med
182
1995
1931
43
Klimpel
GR
Langley
KE
Wypych
J
Abrams
JS
Chopra
AK
Niesel
DW
A role for stem cell factor (SCF ): c-kit interaction(s) in the intestinal tract response to Salmonella typhimurium infection.
J Exp Med
184
1996
271
44
deCastro
CM
Denning
SM
Langdon
S
Vandenbark
GR
Kurtzberg
J
Scearce
R
Haynes
BF
Kaufman
RE
The c-kit proto-oncogene receptor is expressed on a subset of human CD3−CD4−CD8− (triple-negative) thymocytes.
Exp Hematol
22
1994
1025
45
Tajima
Y
Onoue
H
Kitamura
Y
Nishimune
Y
Biologically active kit ligand growth factor is produced by mouse Sertoli cells and is defective in Sld mutant mice.
Development
113
1991
1031
46
Manova
K
Huang
EJ
Angeles
M
De Leon
V
Sanchez
S
Pronovost
SM
Besmer
P
Bachvarova
RF
The expression pattern of the c-kit ligand in gonads of mice supports a role for the c-kit receptor in oocyte growth and in proliferation of spermatogonia.
Development
157
1993
85
47
Manova
K
Bachvarova
RF
Huang
EJ
Sanchez
S
Pronovost
SM
Velazquez
E
McGuire
B
Besmer
P
c-kit receptor and ligand expression in postnatal development of the mouse cerebellum suggests a function for c-kit in inhibitory interneurons.
J Neurosci
12
1992
4663
48
Ratajczak
MZ
Kuczynski
WI
Sokol
DL
Moore
JS
Pletcher
CH Jr
Gewirtz
AM
Expression and physiologic significance of Kit ligand and stem cell tyrosine kinase-1 receptor ligand in normal human CD34+, c-Kit+ marrow cells.
Blood
86
1995
2161
49
Broudy
VC
Kaushansky
K
Harlan
JM
Adamson
JW
Interleukin-1 stimulates human endothelial cells to produce granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor.
J Immunol
139
1987
464
50
Heinrich
MC
Dooley
DC
Keeble
WW
Transforming growth factor 1 inhibits expression of the gene products for steel factor and its receptor (c-kit).
Blood
85
1995
1769
51
Langley
KE
Bennett
LG
Wypych
J
Yancik
SA
Liu
X-D
Westcott
KR
Chang
DG
Smith
KA
Zsebo
KM
Soluble stem cell factor in human serum.
Blood
81
1993
656
52
Wodnar-Filipowicz
A
Yancik
S
Moser
Y
dalle Carbonare V
Gratwohl
A
Tichelli
A
Speck
B
Nissen
C
Levels of soluble stem cell factor in serum of patients with aplastic anemia.
Blood
81
1993
3259
53
Bowen
D
Yancik
S
Bennett
L
Culligan
D
Resser
K
Serum stem cell factor concentration in patients with myelodysplastic syndromes.
Br J Haematol
85
1993
63
54
Abkowitz
JL
Hume
H
Yancik
SA
Bennett
LG
Matsumoto
AM
Stem cell factor serum levels may not be clinically relevant.
Blood
87
1996
4017
55
Testa
U
Martucci
R
Rutella
S
Scambia
G
Sica
S
Panici
PB
Pierelli
L
Menichella
G
Leone
G
Mancuso
S
Peschle
C
Autologous stem cell transplantation: Release of early and late acting growth factors relates with hematopoietic ablation and recovery.
Blood
84
1994
3532
56
Hunt
P
Zsebo
KM
Hokom
MM
Hornkohl
A
Birkett
NC
del Castillo
JC
Martin
F
Evidence that stem cell factor is involved in the rebound thrombocytosis that follows 5-Fluorouracil treatment.
Blood
80
1992
904
57
Limmani
A
Baker
WH
Chang
CM
Seemann
R
Williams
DE
Patchen
ML
c-kit ligand gene expression in normal and sublethally irradiated mice.
Blood
85
1995
2377
58
Arakawa
T
Yphantis
DA
Lary
JW
Narhi
LO
Lu
HS
Prestrelski
SJ
Clogston
CL
Zsebo
KM
Mendiaz
EA
Wypych
J
Langley
KE
Glycosylated and unglycosylated recombinant-derived human stem cell factors are dimeric and have extensive regular secondary structure.
J Biol Chem
266
1991
18942
59
Zsebo
KM
Wypych
J
McNiece
IK
Lu
HS
Smith
KA
Karkare
SB
Sachdev
RK
Yuschenkoff
VN
Birkett
NC
Williams
LR
Satyagal
VN
Tung
W
Bosselman
RA
Mendiaz
EA
Langley
KE
Identification, purification, and biological characterization of hematopoietic stem cell factor from buffalo rat liver-conditioned medium.
Cell
63
1990
195
60
Lu
HS
Clogston
CL
Wypych
J
Fausset
PR
Lauren
S
Mendiaz
EA
Zsebo
KM
Langley
KE
Amino acid sequence and post-translational modification of stem cell factor isolated from Buffalo rat liver cell-conditioned medium.
J Biol Chem
266
1991
8102
61
Lu
HS
Clogston
CL
Wypych
J
Parker
VP
Lee
TD
Swiderek
K
Baltera
RF Jr
Patel
AC
Chang
DC
Brankow
DW
Liu
X-D
Ogden
SG
Karkare
SB
Hu
SS
Zsebo
KM
Langley
KE
Post-translational processing of membrane-associated recombinant human stem cell factor expressed in Chinese hamster ovary cells.
Arch Biochem Biophys
298
1992
150
62
Langley
KE
Wypych
J
Mendiaz
EA
Clogston
CL
Parker
VP
Farrar
DH
Brothers
MO
Satygal
VN
Leslie
I
Birkett
NC
Smith
KA
Baltera
RF Jr
Lyons
DE
Hogan
JM
Crandall
C
Boone
TC
Pope
JA
Karkare
SB
Zsebo
KM
Sachdev
RK
Lu
HS
Purification and characterization of soluble forms of human and rat stem cell factor recombinantly expressed by Escherichia coli and by Chinese hamster ovary cells.
Arch Biochem Biophys
295
1992
21
63
Nishikawa
M
Tojo
A
Ikebuchi
K
Katayama
K
Fujii
N
Ozawa
K
Asano
S
Deletion mutagenesis of stem cell factor defines the c-terminal sequences essential for its biological activity.
Biochem Biophys Res Commun
188
1992
292
64
Jones
MD
Narhi
LO
Chang
W-C
Lu
HS
Refolding and oxidation of recombinant human stem cell factor produced in Escherichia coli.
J Biol Chem
271
1996
11301
65
Lu
HS
Jones
MD
Shieh
J-H
Mendiaz
EA
Feng
D
Watler
P
Narhi
LO
Langley
KE
Isolation and characterization of a disulfide-linked human stem cell factor dimer.
J Biol Chem
271
1996
11309
66
Bazan
JF
Genetic and structural homology of stem cell factor and macrophage colony-stimulating factor.
Cell
65
1991
9
67
Yarden
Y
Kuang
W-J
Yang-Feng
T
Coussens
L
Munemitsu
S
Dull
TJ
Chen
E
Schlessinger
J
Francke
U
Ullrich
A
Human proto-oncogene c-kit: A new cell surface receptor tyrosine kinase for an unidentified ligand.
EMBO J
6
1987
3341
68
Qiu
F
Ray
P
Brown
K
Barker
PE
Jhanwar
S
Ruddle
FH
Besmer
P
Primary structure of c-kit: Relationship with the CSF-1/PDGF receptor kinase family-oncogenic activation of v-kit involves deletion of extracellular domain and C terminus.
EMBO J
7
1988
1003
69
Pandit
J
Bohm
A
Jancarik
J
Halenbeck
R
Koths
K
Kim
S-H
Three-dimensional structure of dimeric human recombinant macrophage colony-stimulating factor.
Science
258
1992
1358
70
Martin
FH
Suggs
SV
Langley
KE
Lu
HS
Ting
J
Okino
KH
Morris
CF
McNiece
IK
Jacobsen
FW
Mendiaz
EA
Birkett
NC
Smith
KA
Johnson
MJ
Parker
VP
Flores
JC
Patel
AC
Fisher
EF
Erjavec
HO
Herrera
CJ
Wypych
J
Sachdev
RK
Pope
JA
Leslie
I
Wen
D
Lin
C-H
Cupples
RL
Zsebo
KM
Primary structure and functional expression of rat and human stem cell factor DNAs.
Cell
63
1990
203
71
Lev
S
Yarden
Y
Givol
D
Dimerization and activation of the Kit receptor by monovalent and bivalent binding of the stem cell factor.
J Biol Chem
267
1992
15970
72
Matous
JV
Langley
K
Kaushansky
K
Structure-function relationships of stem cell factor: An analysis based on a series of human-murine stem cell factor chimera and the mapping of a neutralizing monoclonal antibody.
Blood
88
1996
437
73
Brannan
CI
Bedell
MA
Resnick
JL
Eppig
JJ
Handel
MA
Williams
DE
Lyman
SD
Donovan
PJ
Jenkins
NA
Copeland
NG
Developmental abnormalities in Steel17H mice result from a splicing defect in the steel factor cytoplasmic tail.
Genes Dev
6
1992
1832
74
Langley
KE
Mendiaz
EA
Liu
N
Narhi
LO
Zeni
L
Parseghian
CM
Clogston
CL
Leslie
I
Pope
JA
Lu
HS
Zsebo
KM
Properties of variant forms of human stem cell factor recombinantly expressed in Escherchia coli.
Arch Biochem Biophys
311
1994
55
75
Russell
ES
Bernstein
SE
Lawson
FA
Smith
LJ
Long-continued function of normal blood-forming tissue transplanted into genetically anemic hosts.
J Natl Cancer Inst
23
1959
557
76
Dexter
TM
Moore
MAS
In vitro duplication and ‘cure’ of haemopoietic defects in genetically anaemic mice.
Nature
269
1977
412
77
Bernstein
SE
Tissue transplantation as an analytic and therapeutic tool in hereditary anemias.
Am J Surg
119
1970
448
78
Wolf
NS
Dissecting the hematopoietic microenvironment. III. Evidence for a short range stimulus for cellular proliferation.
Cell Tissue Kinet
11
1978
335
79
McCulloch
EA
Siminovitch
L
Till
JE
Spleen-colony formation in anemic mice of genotype WWV.
Science
144
1964
844
80
Lewis
JP
O'Grady
LF
Bernstein
SE
Russell
ES
Trobaugh
FE Jr
Growth and differentiation of transplanted W/Wv marrow.
Blood
30
1967
601
81
Iscove NN: Committed erythroid precursor populations in genetically anemic W/Wv and Sl/Sld mice, in Hibino S, Takaku F, Shahidi NT (eds): Aplastic Anemia. Baltimore, MD, University Park, 1978
82
Gregory
CJ
Eaves
AC
Three stages of erythropoietic progenitor cell differentiation distinguished by a number of physical and biologic properties.
Blood
51
1978
527
83
Barker
JE
Sl/Sld hematopoietic progenitors are deficient in situ.
Exp Hematol
22
1994
174
84
Leary
AG
Zeng
HQ
Clark
SC
Ogawa
M
Growth factor requirements for survival in G0 and entry into the cell cycle of primitive human hemopoietic progenitors.
Proc Natl Acad Sci USA
89
1992
4013
85
Li
CL
Johnson
GR
Stem cell factor enhances the survival but not the self-renewal of murine hematopoietic long-term repopulating cells.
Blood
84
1994
408
86
Rebel
VI
Dragowska
W
Eaves
CJ
Humphries
RK
Lansdorp
PM
Amplification of Sca-1+ Lin− WGA+ cells in serum-free cultures containing Steel factor, interleukin-6, and erythropoietin with maintenance of cells with long-term in vivo reconstituting potential.
Blood
83
1994
128
87
Wineman
JP
Nishikawa
S-I
Müller-Sieburg
CE
Maintenance of high levels of pluripotent hematopoietic stem cells in vitro: Effect of stromal cells and c-kit.
Blood
81
1993
365
88
Peters
SO
Kittler
ELW
Ramshaw
HS
Quesenberry
PJ
Ex vivo expansion of murine marrow cells with interleukin-3 (IL-3), IL-6, IL-11, and stem cell factor leads to impaired engraftment in irradiated hosts.
Blood
87
1996
30
89
Hirayama
F
Clark
SC
Ogawa
M
Negative regulation of early B lymphopoiesis by interleukin 3 and interleukin 1α.
Proc Natl Acad Sci USA
91
1994
469
90
Hirayama
F
Ogawa
M
Negative regulation of early T lymphopoiesis by interleukin-3 and interleukin-1α.
Blood
86
1995
4527
91
Yonemura
Y
Ku
H
Hirayama
F
Souza
LM
Ogawa
M
Interleukin 3 or interleukin 1 abrogates the reconstituting ability of hematopoietic stem cells.
Proc Natl Acad Sci USA
93
1996
4040
92
Holyoake
TL
Freshney
MG
McNair
L
Parker
AN
McKay
PJ
Steward
WP
Fitzsimons
E
Graham
GJ
Pragnell
IB
Ex vivo expansion with stem cell factor and interleukin-11 augments both short-term recovery posttransplant and the ability to serially transplant marrow.
Blood
87
1996
4589
93
Miller
CL
Rebel
VI Helgason CD
Lansdorp
PM
Eaves
CJ
Impaired steel factor responsiveness differentially affects the detection and long-term maintenance of fetal liver hematopoietic stem cells in vivo.
Blood
89
1997
1214
94
de Vries
P
Brasel
KA
Eisenman
JR
Alpert
AR
Williams
DE
The effect of recombinant mast cell growth factor on purified murine hematopoietic stem cells.
J Exp Med
173
1991
1205
95
Kodama
H
Nose
M
Yamaguchi
Y
Tsunoda
J
Suda
T
Nishikawa
S
Nishikawa
S
In vitro proliferation of primitive hemopoietic stem cells supported by stromal cells: Evidence for the presence of a mechanism(s) other than that involving c-kit receptor and its ligand.
J Exp Med
176
1992
351
96
Sutherland
HJ
Hogge
DE
Cook
D
Eaves
CJ
Alternative mechanisms with and without steel factor support primitive human hematopoiesis.
Blood
81
1993
1465
97
Petzer
AL
Hogge
DE
Lansdorp
PM
Reid
DS
Eaves
CJ
Self-renewal of primitive human hematopoietic cells (long-term-culture-initiating cells) in vitro and their expansion in defined medium.
Proc Natl Acad Sci USA
93
1996
1470
98
Bernstein
ID
Andrews
RG
Zsebo
KM
Recombinant human stem cell factor enhances the formation of colonies by CD34+ and CD34+lin− cells, and the generation of colony-forming cell progeny from CD34+lin− cells cultured with interleukin-3, granulocyte colony-stimulating factor, or granulocyte-macrophage colony-stimulating factor.
Blood
77
1991
2316
99
Migliaccio
G
Migliaccio
AR
Druzin
ML
Giardina
P-JV
Zsebo
KM
Adamson
JW
Long-term generation of colony-forming cells in liquid culture of CD34+ cord blood cells in the presence of recombinant human stem cell factor.
Blood
79
1992
2620
100
Haylock
DN
To
LB
Dowse
TL
Juttner
CA
Simmons
PJ
Ex vivo expansion and maturation of peripheral blood CD34+ cells into the myeloid lineage.
Blood
80
1992
1405
101
Brandt
J
Briddell
RA
Srour
EF
Leemhuis
TB
Hoffman
R
Role of c-kit ligand in the expansion of human hematopoietic progenitor cells.
Blood
79
1992
634
102
Brugger
W
Möcklin
W
Heimfeld
S
Berenson
RJ
Mertelsmann
R
Kanz
L
Ex vivo expansion of enriched peripheral blood CD34+ progenitor cells by stem cell factor, interleukin-1β (IL-1β), IL-6, IL-3, interferon-γ, and erythropoietin.
Blood
81
1993
2579
103
Henschler
R
Brugger
W
Luft
T
Frey
T
Mertelsmann
R
Kanz
L
Maintenance of transplantation potential in ex vivo expanded CD34+-selected human peripheral blood progenitor cells.
Blood
84
1994
2898
104
Brugger
W
Heimfeld
S
Berenson
RJ
Mertelsmann
R
Kanz
L
Reconstitution of hematopoiesis after high-dose chemotherapy by autologous progenitor cells generated ex vivo.
N Engl J Med
333
1995
283
105
Sato
N
Sawada
K
Koizumi
K
Tarumi
T
Ieko
M
Yasukouchi
T
Yamaguchi
M
Takahashi
TA
Sekiguchi
S
Koike
T
In vitro expansion of human peripheral blood CD34+ cells.
Blood
82
1993
3600
106
Shapiro
F
Yao
T-J
Raptis
G
Reich
L
Norton
L
Moore
MAS
Optimization of conditions for ex vivo expansion of CD34+ cells from patients with stage IV breast cancer.
Blood
84
1994
3567
107
Sui
X
Tsuji
K
Tanaka
R
Tajima
S
Muraoka
K
Ebihara
Y
Ikebuchi
K
Yasukawa
K
Taga
T
Kishimoto
T
Nakahata
T
gp130 and c-Kit signalings synergize for ex vivo expansion of human primitive hemopoietic progenitor cells.
Proc Natl Acad Sci USA
92
1995
2859
108
Kobayashi
M
Laver
JH
Kato
T
Miyazaki
H
Ogawa
M
Thrombopoietin supports proliferation of human primitive hematopoietic cells in synergy with steel factor and/or interleukin-3.
Blood
88
1996
429
109
Nocka
K
Buck
J
Levi
E
Besmer
P
Candidate ligand for the c-kit transmembrane kinase receptor: KL, a fibroblast derived growth factor stimulates mast cells and erythroid progenitors.
EMBO J
9
1990
3287
110
Broxmeyer
HE
Hangoc
G
Cooper
S
Anderson
D
Cosman
D
Lyman
SD
Williams
DE
Influence of murine mast cell growth factor (c-kit ligand) on colony formation by mouse marrow hematopoietic progenitor cells.
Exp Hematol
19
1991
143
111
McNiece
IK
Langley
KE
Zsebo
KM
Recombinant human stem cell factor synergises with GM-CSF, G-CSF, IL-3 and Epo to stimulate human progenitor cells of the myeloid and erythroid lineages.
Exp Hematol
19
1991
226
112
Broxmeyer
HE
Cooper
S
Lu
L
Hangoc
G
Anderson
D
Cosman
D
Lyman
SD
Williams
DE
Effect of murine mast cell growth factor (c-kit proto-oncogene ligand) on colony formation by human marrow hematopoietic progenitor cells.
Blood
77
1991
2142
113
Migliaccio
G
Migliaccio
AR
Druzin
ML
Giardina
P-JV
Zsebo
KM
Adamson
JW
Effects of recombinant human stem cell factor (SCF ) on the growth of human progenitor cells in vitro.
J Cell Physiol
148
1991
503
114
Metcalf
D
Nicola
NA
Direct proliferative actions of stem cell factor on murine bone marrow cells in vitro: Effects of combination with colony-stimulating factors.
Proc Natl Acad Sci USA
88
1991
6239
115
Lemoli
RM
Fortuna
A
Fogli
M
Motta
MR
Rizzi
S
Benini
C
Tura
S
Stem cell factor (c-kit ligand) enhances the interleukin-9-dependent proliferation of human CD34+ and CD34+CD33−DR− cells.
Exp Hematol
22
1994
919
116
Fahlman
C
Blomhoff
HK
Veiby
OP
McNiece
IK
Jacobsen
SEW
Stem cell factor and interleukin-7 synergize to enhance early myelopoiesis in vitro.
Blood
84
1994
1450
117
Keller
JR
Ortiz
M
Ruscetti
FW
Steel factor (c-kit ligand) promotes the survival of hematopoietic stem/progenitor cells in the absence of cell division.
Blood
86
1995
1757
118
Dai
CH
Krantz
SB
Zsebo
KM
Human burst-forming units-erythroid need direct interaction with stem cell factor for further development.
Blood
78
1991
2493
119
Papayannopoulou
T
Brice
M
Blau
CA
Kit ligand in synergy with interleukin-3 amplifies the erythropoietin-independent, globin-synthesizing progeny of normal human burst-forming units-erythroid in suspension cultures: Physiologic implications.
Blood
81
1993
299
120
Nocka
K
Majumder
S
Chabot
B
Ray
P
Cervone
M
Bernstein
A
Besmer
P
Expression of c-kit gene products in known cellular targets of W mutations in normal and W mutant mice-evidence for an impaired c-kit kinase in mutant mice.
Genes Dev
3
1989
816
121
de Wolf
JTM
Muller
EW
Hendriks
DH
Halie
RM
Vellenga
E
Mast cell growth factor modulates CD36 antigen expression on erythroid progenitors from human bone marrow and peripheral blood associated with ongoing differentiation.
Blood
84
1994
59
122
Muta
K
Krantz
SB
Bondurant
MC
Wickrema
A
Distinct roles of erythropoietin, insulin-like growth factor I, and stem cell factor in the development of erythroid progenitor cells.
J Clin Invest
94
1994
34
123
Wu
H
Klingmüller
U
Besmer
P
Lodish
HF
Interaction of the erythropoietin and stem-cell-factor receptors.
Nature
377
1995
242
124
Wu
H
Klingmüller
U
Acurio
A
Hsiao
JG
Lodish
HF
Functional interaction of erythropoietin and stem cell factor receptors is essential for erythroid colony formation.
Proc Natl Acad Sci USA
94
1997
1806
125
Sui
X
Tsuji
K
Tajima
S
Tanaka
R
Muraoka
K
Ebihara
Y
Ikebuchi
K
Yasukawa
K
Taga
T
Kishimoto
T
Nakahata
T
Erythropoietin-independent erythrocyte production: Signals through gp130 and c-kit dramatically promote erythropoiesis from human CD34+ cells.
J Exp Med
183
1996
837
126
Peschle
C
Gabbianelli
M
Testa
U
Pelosi
E
Barberi
T
Fossati
C
Valtieri
M
Leone
L
c-kit ligand reactivates fetal hemoglobin synthesis in serum-free culture of stringently purified normal adult burst-forming unit-erythroid.
Blood
81
1993
328
127
Muta
K
Krantz
SB
Bondurant
MC
Dai
C-H
Stem cell factor retards differentiation of normal human erythroid progenitor cells while stimulating proliferation.
Blood
86
1995
572
128
Okumura
N
Tsuji
K
Ebihara
Y
Tanaka
I
Sawai
N
Koike
K
Komiyama
A
Nakahata
T
Chemotactic and chemokinetic activities of stem cell factor on murine hematopoietic progenitor cells.
Blood
87
1996
4100
129
Broudy
VC
Lin
NL
Kaushansky
K
Thrombopoietin (c-mpl ligand) acts synergistically with erythropoietin, stem cell factor, and interleukin-11 to enhance murine megakaryocyte colony growth and increases megakaryocyte ploidy in vitro.
Blood
85
1995
1719
130
Briddell
RA
Bruno
E
Cooper
RJ
Brandt
JE
Hoffman
R
Effect of c-kit ligand on in vitro human megakaryocytopoiesis.
Blood
78
1991
2854
131
Avraham
H
Vannier
E
Cowley
S
Jiang
S
Chi
S
Dinarello
CA
Zsebo
KM
Groopman
JE
Effects of the stem cell factor, c-kit ligand, on human megakaryocytic cells.
Blood
79
1992
365
132
Debili
N
Massé
J-M
Katz
A
Guichard
J
Breton-Gorius
J
Vainchenker
W
Effects of the recombinant hematopoietic growth factors interleukin-3, interleukin-6, stem cell factor, and leukemia inhibitory factor on the megakaryocytic differentiation of CD34+ cells.
Blood
82
1993
84
133
Grabarek
J
Groopman
JE
Lyles
YR
Jiang
S
Bennett
L
Zsebo
K
Avraham
H
Human kit ligand (stem cell factor) modulates platelet activation in vitro.
J Biol Chem
269
1994
21718
134
Kitamura
Y
Go
S
Hatanaka
K
Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation.
Blood
52
1978
447
135
Kitamura
Y
Go
S
Decreased production of mast cells in Sl/Sld anemic mice.
Blood
53
1979
492
136
Suda
T
Suda
J
Spicer
SS
Ogawa
M
Proliferation and differentiation in culture of mast cell progenitors derived from mast cell-deficient mice of genotype W/Wv.
J Cell Physiol
122
1985
187
137
Jarboe
DL
Huff
TF
The mast cell-committed progenitor: W/Wv mice do not make mast cell-committed progenitors and Sl/Sld fibroblasts do not support development of normal mast cell-committed progenitors.
J Immunol
142
1989
2418
138
Tsai
M
Takeishi
T
Thompson
H
Langley
KE
Zsebo
KM
Metcalfe
DD
Geissler
EN
Galli
SJ
Induction of mast cell proliferation, maturation, and heparin synthesis by the rat c-kit ligand, stem cell factor.
Proc Natl Acad Sci USA
88
1991
6382
139
Iemura
A
Tsai
M
Ando
A
Wershil
BK
Galli
SJ
The c-kit ligand, stem cell factor, promotes mast cell survival by suppressing apoptosis.
Am J Pathol
144
1994
321
140
Rodewald
H-R
Dessing
M
Dvorak
AM
Galli
SJ
Identification of a committed precursor for the mast cell lineage.
Science
271
1996
818
141
Kirshenbaum
AS
Goff
JP
Kessler
SW
Mican
JM
Zsebo
KM
Metcalfe
DD
Effect of IL-3 and stem cell factor on the appearance of human basophils and mast cells from CD34+ pluripotent progenitor cells.
J Immunol
148
1992
772
142
Valent
P
Spanblöchl
E
Sperr
WR
Sillaber
C
Zsebo
KM
Agis
H
Strobl
H
Geissler
K
Bettelheim
P
Lechner
K
Induction of differentiation of human mast cells from bone marrow and peripheral blood mononuclear cells by recombinant human stem cell factor/kit-ligand in long-term culture.
Blood
80
1992
2237
143
Durand
B
Migliaccio
G
Yee
NS
Eddleman
K
Huima-Byron
T
Migliaccio
AR
Adamson
JW
Long-term generation of human mast cells in serum-free cultures of CD34+ cord blood cells stimulated with stem cell factor and interleukin-3.
Blood
84
1994
3667
144
Irani
A-MA
Nilsson
G
Miettinen
U
Craig
SS
Ashman
LK
Ishizaka
T
Zsebo
KM
Schwartz
LB
Recombinant human stem cell factor stimulates differentiation of mast cells from dispersed human fetal liver cells.
Blood
80
1992
3009
145
Haig
DM
Huntley
JF
MacKellar
A
Newlands
GFJ
Inglis
L
Sangha
R
Cohen
D
Hapel
A
Galli
SJ
Miller
HRP
Effects of stem cell factor (Kit-ligand) and interleukin-3 on the growth and serine proteinase expression of rat bone marrow-derived or serosal mast cells.
Blood
83
1994
72
146
Rennick
D
Hunte
B
Holland
G
Thompson-Snipes
L
Cofactors are essential for stem cell factor-dependent growth and maturation of mast cell progenitors: Comparative effects of interleukin-3 (IL-3), IL-4, IL-10, and fibroblasts.
Blood
85
1995
57
147
Wershil
BK
Tsai
M
Geissler
EN
Zsebo
KM
Galli
SJ
The rat c-kit ligand, stem cell factor, induces c-kit receptor-dependent mouse mast cell activation in vivo. evidence that signaling through the c-kit receptor can induce expression of cellular function.
J Exp Med
175
1992
245
148
Columbo
M
Horowitz
EM
Botana
LM
MacGlashan
DW Jr
Bochner
BS
Gillis
S
Zsebo
KM
Galli
SJ
Lichtenstein
LM
The human recombinant c-kit receptor ligand, rhSCF, induces mediator release from human cutaneous mast cells and enhances IgE-dependent mediator release from both skin mast cells and peripheral blood basophils.
J Immunol
149
1992
599
149
Meininger
CJ
Yano
H
Rottapel
R
Bernstein
A
Zsebo
KM
Zetter
BR
The c-kit receptor ligand functions as a mast cell chemoattractant.
Blood
79
1992
958
150
Dastych
J
Metcalfe
DD
Stem cell factor induces mast cell adhesion to fibronectin.
J Immunol
152
1994
213
151
Bischoff
SC
Dahinden
CA
c-kit ligand: A unique potentiator of mediator release by human lung mast cells.
J Exp Med
175
1992
237
152
Gagari
E
Tsai
M
Lantz
CS
Fox
LG
Galli
SJ
Differential release of mast cell interleukin-6 via c-kit.
Blood
89
1997
2654
153
Galli
SJ
Iemura
A
Garlick
DS
Gamba-Vitalo
C
Zsebo
KM
Andrews
RG
Reversible expansion of primate mast cell populations in vivo by stem cell factor.
J Clin Invest
91
1993
148
154
Tsai
M
Shih
L-S
Newlands
GFJ
Takeishi
T
Langley
KE
Zsebo
KM
Miller
HRP
Geissler
EN
Galli
SJ
The rat c-kit ligand, stem cell factor, induces the development of connective tissue-type and mucosal mast cells in vivo. Analysis by anatomical distribution, histochemistry, and protease phenotype.
J Exp Med
174
1991
125
155
Costa
JJ
Demetri
GD
Harrist
TJ
Dvorak
AM
Hayes
DF
Merica
EA
Menchaca
DM
Gringeri
AJ
Schwartz
LB
Galli
SJ
Recombinant human stem cell factor (Kit ligand) promotes human mast cell and melanocyte hyperplasia and funcational activation in vivo.
J Exp Med
183
1996
2681
156
Opstelten
D
Osmond
DG
Regulation of pre-B cell proliferation in bone marrow: Immunofluorescence stathmokinetic studies of cytoplasmic μ chain-bearing cells in anti-IgM-treated mice, hematologically deficient mutant mice and mice given sheep red blood cells.
Eur J Immunol
15
1985
599
157
Landreth
KS
Kincade
PW
Lee
G
Harrison
DE
B lymphocyte precursors in embryonic and adult W anemic mice.
J Immunol
132
1984
2724
158
Rico-Vargas
SA
Weiskopf
B
Nishikawa
S-I
Osmond
DG
c-kit expression by B cell precursors in mouse bone marrow.
J Immunol
152
1994
2845
159
Takeda
S
Shimizu
S
Rodewald
H-R
Interactions between c-kit and stem cell factor are not required for B-cell development in vivo.
Blood
89
1997
518
160
Rolink
A
Melchers
F
Molecular and cellular origins of B lymphocyte diversity.
Cell
66
1991
1081
161
Hirayama
F
Shih
J-P
Awgulewitsch
A
Warr
GW
Clark
SC
Ogawa
M
Clonal proliferation of murine lymphohemopoietic progenitors in culture.
Proc Natl Acad Sci USA
89
1992
5907
162
Veiby
OP
Lyman
SD
Jacobsen
SEW
Combined signaling through interleukin-7 receptors and flt3 but not c-kit potently and selectively promotes B-cell commitment and differentiation from uncommitted murine bone marrow progenitor cells.
Blood
88
1996
1256
163
Faust
EA
Saffran
DC
Toksoz
D
Williams
DA
Witte
ON
Distinctive growth requirements and gene expression patterns distinguish progenitor B cells from pre-B cells.
J Exp Med
177
1993
915
164
Billips
LG
Petitte
D
Dorshkind
K
Narayanan
R
Chiu
C-P
Landreth
KS
Differential roles of stromal cells, interleukin-7, and kit-ligand in the regulation of B lymphopoiesis.
Blood
79
1992
1185
165
Rolink
A
Streb
M
Nishikawa
S-I
Melchers
F
The c-kit-encoded tyrosine kinase regulates the proliferation of early pre-B cells.
Eur J Immunol
21
1991
2609
166
Rodewald
H-R
Kretzschmar
K
Swat
W
Takeda
S
Intrathymically expressed c-kit ligand (stem cell factor) is a major factor driving expansion of very immature thymocytes in vivo.
Immunity
3
1995
313
167
Godfrey
DI
Zlotnik
A
Suda
T
Phenotypic and functional characterization of c-kit expression during intrathymic T cell development.
J Immunol
149
1992
2281
168
Laky
K
Lefrancois
L
Puddington
L
Age-dependent intestinal lymphoproliferative disorder due to stem cell factor receptor deficiency.
J Immunol
158
1997
1417
169
Bluman
EM
Schnier
GS
Avalos
BR
Strout
MP
Sultan
H
Jacobson
FW
Williams
DE
Carson
WE
Caligiuri
MA
The c-kit ligand potentiates the allogeneic mixed lymphocyte reaction.
Blood
88
1996
3887
170
Shibuya
A
Nagayoshi
K
Nakamura
K
Nakauchi
H
Lymphokine requirement for the generation of natural killer cells from CD34+ hematopoietic progenitor cells.
Blood
85
1995
3538
171
Matos
ME
Schnier
GS
Beecher
MS
Ashman
LK
Williams
DE
Caligiuri
MA
Expression of a functional c-kit receptor on a subset of natural killer cells.
J Exp Med
178
1993
1079
172
Young
JW
Szabolcs
P
Moore
MAS
Identification of dendritic cell colony-forming units among normal human CD34+ bone marrow progenitors that are expanded by c-kit-ligand and yield pure dendritic cell colonies in the presence of granulocyte/macrophage colony-stimulating factor and tumor necrosis factor α.
J Exp Med
182
1995
1111
173
Szabolcs
P
Moore
MAS
Young
JW
Expansion of immunostimulatory dendritic cells among the myeloid progeny of human CD34+ bone maarrow precursors cultured with c-kit ligand, granulocyte-macrophage colony-stimulating factor, and TNF-α.
J Immunol
154
1995
5851
174
Yoder
MC
Williams
DA
Matrix molecule interactions with hematopoietic stem cells.
Exp Hematol
23
1995
961
175
Rosemblatt
M
Vuillet-Gaugler
MH
Leroy
C
Coulombel
L
Coexpression of two fibronectin receptors, VLA-4 and VLA-5, by immature human erythroblastic precursor cells.
J Clin Invest
87
1991
6
176
Simmons
PJ
Masinovsky
B
Longenecker
BM
Berenson
R
Torok-Storb
B
Gallatin
WM
Vascular cell adhesion molecule-1 expressed by bone marrow stromal cells mediates the binding of hematopoietic progenitor cells.
Blood
80
1992
388
177
Verfaillie
CM
McCarthy
JB
McGlave
PB
Differentiation of primitive human multipotent hematopoietic progenitors into single lineage clonogenic progenitors is accompanied by alterations in their interaction with fibronectin.
J Exp Med
174
1991
693
178
Williams
DA
Rios
M
Stephens
C
Patel
VP
Fibronectin and VLA-4 in haematopoietic stem cell-microenvironment interactions.
Nature
352
1991
438
179
Vuillet-Gaugler
MH
Breton-Gorius
J
Vainchenker
W
Guichard
J
Leroy
C
Tchernia
G
Coulombel
L
Loss of attachment to fibronectin with terminal human erythroid differentiation.
Blood
75
1990
865
180
Hurley
RW
McCarthy
JB
Verfaillie
CM
Direct adhesion to bone marrow stroma via fibronectin receptors inhibits hematopoietic progenitor proliferation.
J Clin Invest
96
1995
511
181
Healy
L
May
G
Gale
K
Grosveld
F
Greaves
M
Enver
T
The stem cell antigen CD34 functions as a regulator of hemopoietic cell adhesion.
Proc Natl Acad Sci USA
92
1995
12240
182
Kinashi
T
Springer
TA
Steel factor and c-kit regulate cell-matrix adhesion.
Blood
83
1994
1033
183
Kaneko
Y
Takenawa
J
Yoshida
O
Fujita
K
Sugimoto
K
Nakayama
H
Fujita
J
Adhesion of mouse mast cells to fibroblasts: Adverse effects of steel (Sl) mutation.
J Cell Physiol
147
1991
224
184
Adachi
S
Ebi
Y
Nishikawa
S
Hayashi
S
Yamazaki
M
Kasugai
T
Yamamura
T
Nomura
S
Kitamura
Y
Necessity of extracellular domain of W (c-kit) receptors for attachment of murine cultured mast cells to fibroblasts.
Blood
79
1992
650
185
Serve
H
Yee
NS
Stella
G
Sepp-Lorenzino
L
Tan
JC
Besmer
P
Differential roles of PI3-kinase and Kit tyrosine 821 in Kit receptor-mediated proliferation, survival and cell adhesion in mast cells.
EMBO J
14
1995
473
186
Kovach
NL
Lin
N
Yednock
T
Harlan
JM
Broudy
VC
Stem cell factor modulates avidity of α4β1 and α5β1 integrins expressed on hematopoietic cell lines.
Blood
85
1995
159
187
Lévesque
J-P
Leavesley
DI
Niutta
S
Vadas
M
Simmons
PJ
Cytokines increase human hemopoietic cell adhesiveness by activation of very late antigen (VLA)-4 and VLA-5 integrins.
J Exp Med
181
1995
1805
188
Lévesque
J-P
Haylock
DN
Simmons
PJ
Cytokine regulation of proliferation and cell adhesion are correlated events in human CD34+ hemopoietic progenitors.
Blood
88
1996
1168
189
Kodama
H
Nose
M
Niida
S
Nishikawa
S
Nishikawa
S-I
Involvement of the c-kit receptor in the adhesion of hematopoietic stem cells to stromal cells.
Exp Hematol
22
1994
979
190
Avraham
H
Scadden
DT
Chi
S
Broudy
VC
Zsebo
KM
Groopman
JE
Interaction of human bone marrow fibroblasts with megakaryocytes: Role of the c-kit ligand.
Blood
80
1992
1679
191
Takahira
H
Gotoh
A
Ritchie
A
Broxmeyer
HE
Steel factor enhances integrin-mediated tyrosine phosphorylation of focal adhesion kinase (pp125FAK) and paxillin.
Blood
89
1997
1574
192
Anklesaria P, Greenberger J, Pratt DBC, Fitzgerald TJ, Sullenbarger B, Campbell A, Williams D, Wicha M: Steel factor induces a marrow specific adhesion protein hemonectin in stromal cell lines from Sl/Sld mice. Exp Hematol 20:807, 1992 (abstr)
193
Anklesaria
P
Greenberger
JS
Fitzgerald
TJ
Sullenbarger
B
Wicha
M
Campbell
A
Hemonectin mediates adhesion of engrafted murine progenitors to a clonal bone marrow stromal cell line from Sl/Sld mice.
Blood
77
1991
1691
194
Blume-Jensen
P
Claesson-Welsh
L
Siegbahn
A
Zsebo
KM
Westermark
B
Heldin
C-H
Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis.
EMBO J
10
1991
4121
195
Fleming
WH
Alpern
EJ
Uchida
N
Ikuta
K
Weissman
IL
Steel factor influences the distribution and activity of murine hematopoietic stem cells in vivo.
Proc Natl Acad Sci USA
90
1993
3760
196
Yan
X-Q
Briddell
R
Hartley
C
Stoney
G
Samal
B
McNiece
I
Mobilization of long-term hematopoietic reconstituting cells in mice by the combination of stem cell factor plus granulocyte colony-stimulating factor.
Blood
84
1994
795
197
Andrews
RG
Bartelmez
SH
Knitter
GH
Myerson
D
Bernstein
ID
Appelbaum
FR
Zsebo
KM
A c-kit ligand, recombinant human stem cell factor, mediates reversible expansion of multiple CD34+ colony-forming cell types in blood and marrow of baboons.
Blood
80
1992
920
198
Andrews
RG
Bensinger
WI
Knitter
GH
Bartelmez
SH
Longin
K
Bernstein
ID
Appelbaum
FR
Zsebo
KM
The ligand for c-kit, stem cell factor, stimulates the circulation of cells that engraft lethally irradiated baboons.
Blood
80
1992
2715
199
Papayannopoulou
T
Nakamoto
B
Peripheralization of hemopoietic progenitors in primates treated with anti-VLA4 integrin.
Proc Natl Acad Sci USA
90
1993
9374
200
Papayannopoulou
T
Craddock
C
Nakamoto
B
Priestley
G
Wolf
NS
The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen.
Proc Natl Acad Sci USA
92
1995
9647
201
Carlos
TM
Harlan
JM
Leukocyte-endothelial adhesion molecules.
Blood
84
1994
2068
202
Tong
J
Gordon
MS
Srour
EF
Cooper
RJ
Orazi
A
McNiece
I
Hoffman
R
In vivo administration of recombinant methionyl human stem cell factor expands the number of human marrow hematopoietic stem cells.
Blood
82
1993
784
203
Weaver
A
Ryder
D
Crowther
D
Dexter
TM
Testa
NG
Increased numbers of long-term culture-initiating cells in the apheresis product of patients randomized to receive increasing doses of stem cell factor administered in combination with chemotherapy and a standard dose of granulocyte colony-stimulating factor.
Blood
88
1996
3323
204
Bodine
DM
Orlic
D
Birkett
NC
Seidel
NE
Zsebo
KM
Stem cell factor increases colony-forming unit-spleen number in vitro in synergy with interleukin-6, and in vivo in Sl/Sld mice as a single factor.
Blood
79
1992
913
205
Molineux
G
Migdalska
A
Szmitkowski
M
Zsebo
K
Dexter
TM
The effects on hematopoiesis of recombinant stem cell factor (ligand for c-kit) administered in vivo to mice either alone or in combination with granulocyte colony-stimulating factor.
Blood
78
1991
961
206
Bodine
DM
Seidel
NE
Zsebo
KM
Orlic
D
In vivo administration of stem cell factor to mice increases the absolute number of pluripotent hematopoietic stem cells.
Blood
82
1993
445
207
Harrison
DE
Zsebo
KM
Astle
CM
Splenic primitive hematopoietic stem cell (PHSC) activity is enhanced by steel factor because of PHSC proliferation.
Blood
83
1994
3146
208
Bodine
DM
Seidel
NE
Gale
MS
Nienhuis
AW
Orlic
D
Efficient retrovirus transduction of mouse pluripotent hematopoietic stem cells mobilized into the peripheral blood by treatment with granulocyte colony-stimulating factor and stem cell factor.
Blood
84
1994
1482
209
Dunbar
CE
Seidel
NE
Doren
S
Sellers
S
Cline
AP
Metzger
ME
Agricola
BA
Donahue
RE
Bodine
DM
Improved retroviral gene transfer into murine and rhesus peripheral blood or bone marrow repopulating cells primed in vivo with stem cell factor and granulocyte colony-stimulating factor.
Proc Natl Acad Sci USA
93
1996
11871
210
Yan
X-Q
Hartley
C
McElroy
P
Chang
A
McCrea
C
McNiece
I
Peripheral blood progenitor cells mobilized by recombinant human granulocyte colony-stimulating factor plus recombinant rat stem cell factor contain long-term engrafting cells capable of cellular proliferation for more than two years as shown by serial transplantation in mice.
Blood
85
1995
2303
211
Andrews
RG
Briddell
RA
Knitter
GH
Rowley
SD
Appelbaum
FR
McNiece
IK
Rapid engraftment by peripheral blood progenitor cells mobilized by recombinant human stem cell factor and recombinant human granulocyte colony-stimulating factor in nonhuman primates.
Blood
85
1995
15
212
Russell
ES
Bernstein
SE
McFarland
EC
Modeen
WR
The cellular basis of differential radiosensitivity of normal and genetically anemic mice.
Radiat Res
20
1963
677
213
Yee
NS
Paek
I
Besmer
P
Role of kit-ligand in proliferation and suppression of apoptosis in mast cells: Basis for radiosensitivity of White Spotting and Steel mutant mice.
J Exp Med
179
1994
1777
214
Zsebo
KM
Smith
KA
Hartley
CA
Greenblatt
M
Cooke
K
Rich
W
McNiece
IK
Radioprotection of mice by recombinant rat stem cell factor.
Proc Natl Acad Sci USA
89
1992
9464
215
Leigh
BR
Khan
W
Hancock
SL
Knox
SJ
Stem cell factor enhances the survival of murine intestinal stem cells after photon irradiation.
Radiat Res
142
1995
12
216
Patchen
ML
Fischer
R
Schmauder-Chock
EA
Williams
DE
Mast cell growth factor enhances multilineage hematopoietic recovery in vivo following radiation-induced aplasia.
Exp Hematol
22
1994
31
217
Schuening
FG
Appelbaum
FR
Deeg
HJ
Sullivan-Pepe
M
Graham
TC
Hackman
R
Zsebo
KM
Storb
R
Effects of recombinant canine stem cell factor, a c-kit ligand, and recombinant granulocyte colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation.
Blood
81
1993
20
218
Neta
R
Williams
D
Selzer
F
Abrams
J
Inhibition of c-kit ligand/steel factor by antibodies reduces survival of lethally irradiated mice.
Blood
81
1993
324
219
Molineux
G
Migdalska
A
Haley
J
Evans
GS
Dexter
TM
Total marrow failure induced by pegylated stem-cell factor administered before 5-Fluorouracil.
Blood
83
1994
3491
220
Du XX
Keller D
Maze
R
Williams
DA
Comparative effects of in vivo treatment using interleukin-11 and stem factor on reconstitution in mice after bone marrow transplantation.
Blood
82
1993
1016
221
Storb
R
Raff
RF
Appelbaum
FR
Deeg
HJ
Graham
TC
Schuening
FG
Shulman
H
Yu
C
Bryant
E
Burnett
R
Seidel
K
DLA-identical bone marrow grafts after low-dose total body irradiation. The effect of canine recombinant hematopoietic growth factors.
Blood
84
1994
3558
222
Dolci
S
Williams
DE
Ernst
MK
Resnick
JL
Brannan
CI
Lock
LF
Lyman
SD
Boswell
HS
Donovan
PJ
Requirement for mast cell growth factor for primordial germ cell survival in culture.
Nature
352
1991
809
223
Matsui
Y
Toksoz
D
Nishikawa
S
Nishikawa
S-I
Williams
D
Zsebo
K
Hogan
BLM
Effect of steel factor and leukaemia inhibitory factor on murine primordial germ cells in culture.
Nature
353
1991
750
224
Miyazawa
K
Williams
DA
Gotoh
A
Nishimaki
J
Broxmeyer
HE
Toyama
K
Membrane-bound steel factor induces more persistent tyrosine kinase activation and longer life span of c-kit gene-encoded protein than its soluble form.
Blood
85
1995
641
225
Marshall
CJ
Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation.
Cell
80
1995
179
226
Majumdar
MK
Everett
ET
Xiao
X
Cooper
R
Langley
K
Kapur
R
Vik
T
Williams
DA
Xenogeneic expression of human stem cell factor in transgenic mice mimics codominant c-kit mutations.
Blood
87
1996
3203
227
Kapur R, Majumdar MK, Xiao X, Schindler K, McAndrews-Hill M, Williams DA: Transgenic expression of stem cell factor in Steel-dickie mice: Delineation of a unique in vivo role of membrane-associated protein in erythropoiesis. Blood 88:473a, 1996 (abstr, suppl 1)
228
Wehrle-Haller
B
Weston
JA
Soluble and cell-bound forms of steel factor activity play distinct roles in melanocyte precursor dispersal and survival on the lateral neural crest migration pathway.
Development
121
1995
731
229
Besmer
P
Murphy
JE
George
PC
Qiu
F
Bergold
PJ
Lederman
L
Snyder
HW Jr
Brodeur
D
Zuckerman
EE
Hardy
WD
A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family.
Nature
320
1986
415
230
Ullrich
A
Schlessinger
J
Signal transduction by receptors with tyrosine kinase activity.
Cell
61
1990
203
231
Heldin
C-H
Dimerization of cell surface receptors in signal transduction.
Cell
80
1995
213
232
Paulson
RF
Vesely
S
Siminovitch
KA
Bernstein
A
Signalling by the W/Kit receptor tyrosine kinase is negatively regulated in vivo by the protein tyrosine phosphatase Shp1.
Nat Genet
13
1996
309
233
Lorenz
U
Bergemann
AD
Steinberg
HN
Flanagan
JG
Li
X
Galli
SJ
Neel
BG
Genetic analysis reveals cell type-specific regulation of receptor tyrosine kinase c-kit by the protein tyrosine phosphatase SHP1.
J Exp Med
184
1996
1111
234
Blechman
JM
Lev
S
Brizzi
MF
Leitner
O
Pegoraro
L
Givol
D
Yarden
Y
Soluble c-Kit proteins and antireceptor monoclonal antibodies confine the binding site of the stem cell factor.
J Biol Chem
268
1993
4399
235
Lev
S
Blechman
J
Nishikawa
S-I
Givol
D
Yarden
Y
Interspecies molecular chimeras of Kit help define the binding site of the stem cell factor.
Mol Cell Biol
13
1993
2224
236
Blechman
JM
Lev
S
Barg
J
Eisenstein
M
Vaks
B
Vogel
Z
Givol
D
Yarden
Y
The fourth immunoglobulin domain of the stem cell factor receptor couples ligand binding to signal transduction.
Cell
80
1995
103
237
Lev
S
Yarden
Y
Givol
D
A recombinant ectodomain of the receptor for the stem cell factor (SCF ) retains ligand-induced receptor dimerization and antagonizes SCF-stimulated cellular responses.
J Biol Chem
267
1992
10866
238
Turner
AM
Bennett
LG
Lin
NL
Wypych
J
Bartley
TD
Hunt
RW
Atkins
HL
Langley
KE
Parker
V
Martin
F
Broudy
VC
Identification and characterization of a soluble c-kit receptor produced by human hematopoietic cell lines.
Blood
85
1995
2052
239
Philo
JS
Wen
J
Wypych
J
Schwartz
MG
Mendiaz
EA
Langley
KE
Human stem cell factor dimer forms a complex with two molecules of the extracellular domain of its receptor, Kit.
J Biol Chem
271
1996
6895
240
Reith
AD
Ellis
C
Lyman
SD
Anderson
DM
Williams
DE
Bernstein
A
Pawson
T
Signal transduction by normal isoforms and W mutant variants of the Kit receptor tyrosine kinase.
EMBO J
10
1991
2451
241
Piao
X
Curtis
JE
Minkin
S
Minden
MD
Bernstein
A
Expression of the Kit and KitA receptor isoforms in human acute myelogenous leukemia.
Blood
83
1994
476
242
Furitsu
T
Tsujimura
T
Tono
T
Ikeda
H
Kitayama
H
Koshimizu
U
Sugahara
H
Butterfield
JH
Ashman
LK
Kanayama
Y
Matsuzawa
Y
Kitamura
Y
Kanakura
Y
Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product.
J Clin Invest
92
1993
1736
243
Tsujimura
T
Furitsu
T
Morimoto
M
Isozaki
K
Nomura
S
Matsuzawa
Y
Kitamura
Y
Kanakura
Y
Ligand-independent activation of c-kit receptor tyrosine kinase in a murine mastocytoma cell line P-815 generated by a point mutation.
Blood
83
1994
2619
244
Hashimoto
K
Tsujimura
T
Moriyama
Y
Yamatodani
A
Kimura
M
Tohya
K
Morimoto
M
Kitayama
H
Kanakura
Y
Kitamura
Y
Transforming and differentiation-inducing potential of constitutively activated c-kit mutant genes in the IC-2 murine interleukin-3-dependent mast cell line.
Am J Pathol
148
1996
189
245
Piao
X
Bernstein
A
A point mutation in the catalytic domain of c-kit induces growth factor independence, tumorigenicity, and differentiation of mast cells.
Blood
87
1996
3117
246
Kitayama
H
Tsujimura
T
Matsumura
I
Oritani
K
Ikeda
H
Ishikawa
J
Okabe
M
Suzuki
M
Yamamura
K-i
Matsuzawa
Y
Kitamura
Y
Kanakura
Y
Neoplastic transformation of normal hematopoietic cells by constitutively activating mutations of c-kit receptor tyrosine kinase.
Blood
88
1996
995
247
Nagata
H
Worobec
AS
Oh
CK
Chowdhury
BA
Tannenbaum
S
Suzuki
Y
Metcalfe
DD
Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder.
Proc Natl Acad Sci USA
92
1995
10560
248
Longley
BJ
Tyrrell
L
Lu
S-Z
Ma
Y-S
Langley
K
Ding
T-g
Duffy
T
Jacobs
P
Tang
LH
Modlin
I
Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: Establishment of clonality in a human mast cell neoplasm.
Nat Genet
12
1996
312
249
Piao
X
Paulson
R
van der Geer
P
Pawson
T
Bernstein
A
Oncogenic mutation in the Kit receptor tyrosine kinase alters substrate specificity and induces degradation of the protein tyrosine phosphatase SHP-1.
Proc Natl Acad Sci USA
93
1996
14665
250
Kitayama
H
Kanakura
Y
Furitsu
T
Tsujimura
T
Oritani
K
Ikeda
H
Sugahara
H
Mitsui
H
Kanayama
Y
Kitamura
Y
Matsuzawa
Y
Constitutively activating mutations of c-kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines.
Blood
85
1995
790
251
Tsujimura
T
Morimoto
M
Hashimoto
K
Moriyama
Y
Kitayama
H
Matsuzawa
Y
Kitamura
Y
Kanakura
Y
Constitutive activation of c-kit in FMA3 murine mastocytoma cells caused by deletion of seven amino acids at the juxtamembrane domain.
Blood
87
1996
273
252
Giebel
LB
Spritz
RA
Mutation of the KIT (mast/stem cell growth factor receptor) protooncogene in human piebaldism.
Proc Natl Acad Sci USA
88
1991
8696
253
Fleischman
RA
Human piebald trait resulting from a dominant negative mutant allele of the c-kit membrane receptor gene.
J Clin Invest
89
1992
1713
254
Spritz
RA
Giebel
LB
Holmes
SA
Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism.
Am J Hum Genet
50
1992
261
255
Spritz
RA
Holmes
SA
Ramesar
R
Greenberg
J
Curtis
D
Beighton
P
Mutations of the KIT (mast/stem cell growth factor receptor) proto-oncogene account for a continuous range of phenotypes in human piebaldism.
Am J Hum Genet
51
1992
1058
256
Okada
S
Nakauchi
H
Nagayoshi
K
Nishikawa
S
Nishikawa
S
Miura
Y
Suda
T
Enrichment and characterization of murine hematopoietic stem cells that express c-kit molecule.
Blood
78
1991
1706
257
Doi
H
Inaba
M
Yamamoto
Y
Taketani
S
Mori
S-I
Sugihara
A
Ogata
H
Toki
J
Hisha
H
Inaba
K
Sogo
S
Adachi
M
Matsuda
T
Good
RA
Ikehara
S
Pluripotent hemopoietic stem cells are c-kit<low.
Proc Natl Acad Sci USA
94
1997
2513
258
Kawashima
I
Zanjani
ED
Almaida-Porada
G
Flake
AW
Zeng
H
Ogawa
M
CD34+ human marrow cells that express low levels of Kit protein are enriched for long-term marrow-engrafting cells.
Blood
87
1996
4136
259
Ikuta
K
Weissman
IL
Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation.
Proc Natl Acad Sci USA
89
1992
1502
260
Li
CL
Johnson
GR
Murine hematopoietic stem and progenitor cells: I. Enrichment and biologic characterization.
Blood
85
1995
1472
261
Jones
RJ
Collector
MI
Barber
JP
Vala
MS
Fackler
MJ
May
WS
Griffin
CA
Hawkins
AL
Zehnbauer
BA
Hilton
J
Colvin
OM
Sharkis
SJ
Characterization of mouse lymphohematopoietic stem cells lacking spleen colony-forming activity.
Blood
88
1996
487
262
Osawa
M
Hanada
K
Hamada
H
Nakauchi
H
Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell.
Science
273
1996
242
263
Osawa
M
Nakamura
K
Nishi
N
Takahashi
N
Tokuomoto
Y
Inoue
H
Nakauchi
H
In vivo self-renewal of c-kit+ Sca-1+ Linlow/− hemopoietic stem cells.
J Immunol
156
1996
3207
264
Ashman
LK
Cambareri
AC
To
LB
Levinsky
RJ
Juttner
CA
Expression of the YB5.B8 antigen (c-kit proto-oncogene product) in normal human bone marrow.
Blood
78
1991
30
265
Broudy
VC
Lin
N
Zsebo
KM
Birkett
NC
Smith
KA
Bernstein
ID
Papayannopoulou
T
Isolation and characterization of a monoclonal antibody that recognizes the human c-kit receptor.
Blood
79
1992
338
266
Papayannopoulou
T
Brice
M
Broudy
VC
Zsebo
KM
Isolation of c-kit receptor-expressing cells from bone marrow, peripheral blood, and fetal liver: Functional properties and composite antigenic profile.
Blood
78
1991
1403
267
Briddell
RA
Broudy
VC
Bruno
E
Brandt
JE
Srour
EF
Hoffman
R
Further phenotypic characterization and isolation of human hematopoietic progenitor cells using a monoclonal antibody to the c-kit receptor.
Blood
79
1992
3159
268
De Jong
MO
Wagemaker
G
Wognum
AW
Separation of myeloid and erythroid progenitors based on expression of CD34 and c-kit.
Blood
86
1995
4076
269
Olweus
J
Terstappen
LWMM
Thompson
PA
Lund-Johansen
F
Expression and function of receptors for stem cell factor and erythropoietin during lineage commitment of human hematopoietic progenitor cells.
Blood
88
1996
1594
270
Yee
NS
Langen
H
Besmer
P
Mechanism of kit ligand, phorbol ester, and calcium-induced down-regulation of c-kit receptors in mast cells.
J Biol Chem
268
1993
14189
271
Katayama
N
Shih
J-P
Nishikawa
S
Kina
T
Clark
SC
Ogawa
M
Stage-specific expression of c-kit protein by murine hematopoietic progenitors.
Blood
82
1993
2353
272
Wang
C
Curtis
JE
Geissler
EN
McCulloch
EA
Minden
MD
The expression of the proto-oncogene c-kit in the blast cells of acute myeloblastic leukemia.
Leukemia
3
1989
699
273
Ikeda
H
Kanakura
Y
Tamaki
T
Kuriu
A
Kitayama
H
Ishikawa
J
Kanayama
Y
Yonezawa
T
Tarui
S
Griffin
JD
Expression and functional role of the proto-oncogene c-kit in acute myeloblastic leukemia cells.
Blood
78
1991
2962
274
Broudy
VC
Smith
FO
Lin
N
Zsebo
KM
Egrie
J
Bernstein
ID
Blasts from patients with acute myelogenous leukemia express functional receptors for stem cell factor.
Blood
80
1992
60
275
Bühring
H-J
Ullrich
A
Schaudt
K
Müller
CA
Busch
FW
The product of the proto-oncogene c-kit (P145c-kit) is a human bone marrow surface antigen of hemopoietic precursor cells which is expressed on a subset of acute non-lymphoblastic leukemic cells.
Leukemia
5
1991
854
276
Pinto
A
Gloghini
A
Gattei
V
Aldinucci
D
Zagonel
V
Carbone
A
Expression of the c-kit receptor in human lymphomas is restricted to Hodgkin's Disease and CD30+ anaplastic large cell lymphomas.
Blood
83
1994
785
277
Tomeczkowski
J
Beilken
A
Frick
D
Wieland
B
König
A
Falk
MH
Reiter
A
Welte
K
Sykora
K-W
Absence of c-kit receptor and absent proliferative response to stem cell factor in childhood Burkitt's lymphoma cells.
Blood
86
1995
1469
278
Hu
Z-B
Ma
W
Uphoff
CC
Quentmeier
H
Drexler
HG
c-kit expression in human megakaryoblastic leukemia cell lines.
Blood
83
1994
2133
279
Abkowitz
JL
Broudy
VC
Bennett
LG
Zsebo
KM
Martin
FH
Absence of abnormalities of c-kit or its ligand in two patients with Diamond-Blackfan anemia.
Blood
79
1992
25
280
Turner
AM
Zsebo
KM
Martin
F
Jacobsen
FW
Bennett
LG
Broudy
VC
Nonhematopoietic tumor cell lines express stem cell factor and display c-kit receptors.
Blood
80
1992
374
281
Cohen
PS
Chan
JP
Lipkunskaya
M
Biedler
JL
Seeger
RC
The
Children's Cancer Group
Expression of stem cell factor and c-kit in human neuroblastoma.
Blood
84
1994
3465
282
Sekido
Y
Obata
Y
Ueda
R
Hida
T
Suyama
M
Shimokata
K
Ariyoshi
Y
Takahashi
T
Preferential expression of c-kit protooncogene transcripts in small cell lung cancer.
Cancer Res
51
1991
2416
283
Natali
PG
Nicotra
MR
Sures
I
Santoro
E
Bigotti
A
Ullrich
A
Expression of c-kit receptor in normal and transformed human nonlymphoid tissues.
Cancer Res
52
1992
6139
284
Strohmeyer
T
Peter
S
Hartmann
M
Munemitsu
S
Ackermann
R
Ullrich
A
Slamon
DJ
Expression of the hst-1 and c-kit protooncogenes in human testicular germ cell tumors.
Cancer Res
51
1991
1811
285
Miyazawa
K
Toyama
K
Gotoh
A
Hendrie
PC
Mantel
C
Broxmeyer
HE
Ligand-dependent polyubiquitination of c-kit gene product: A possible mechanism of receptor down modulation in M07e cells.
Blood
83
1994
137
286
Yee
NS
Hsiau
C-WM
Serve
H
Vosseller
K
Besmer
P
Mechanism of down-regulation of c-kit receptor.
J Biol Chem
269
1994
31991
287
Sorkin
A
Waters
CM
Endocytosis of growth factor receptors.
Bioessays
15
1993
375
288
Dubois
CM
Ruscetti
FW
Stankova
J
Keller
JR
Transforming growth factor-β regulates c-kit message stability and cell-surface protein expression in hematopoietic progenitors.
Blood
83
1994
3138
289
Khoury
E
Andre
C
Pontvert-Delucq
S
Drenou
B
Baillou
C
Guigon
M
Najman
A
Lemoine
FM
Tumor necrosis factor α (TNFα) downregulates c-kit proto-oncogene product expression in normal and acute myeloid leukemia CD34+ cells via p55 TNFα receptors.
Blood
84
1994
2506
290
Sillaber
C
Strobl
H
Bevec
D
Ashman
LK
Butterfield
JH
Lechner
K
Maurer
D
Bettelheim
P
Valent
P
IL-4 regulates c-kit proto-oncogene product expression in human mast and myeloid progenitor cells.
J Immunol
147
1991
4224
291
Rusten
LS
Smeland
EB
Jacobsen
FW
Lien
E
Lesslauer
W
Loetscher
H
Dubois
CM
Jacobsen
SEW
Tumor necrosis factor-α inhibits stem cell factor-induced proliferation of human bone marrow progenitor cells in vitro.
J Clin Invest
94
1994
165
292
Brizzi
MF
Blechman
JM
Cavalloni
G
Givol
D
Yarden
Y
Pegoraro
L
Protein kinase C-dependent release of a functional whole extracellular domain of the mast cell growth factor (MGF ) receptor by MGF-depdendent human myeloid cells.
Oncogene
9
1994
1583
293
Rose-John
S
Heinrich
PC
Soluble receptors for cytokines and growth factors: Generation and biological function.
Biochem J
300
1994
281
294
Heaney
ML
Golde
DW
Soluble cytokine receptors.
Blood
87
1996
847
295
Peters
M
Jacobs
S
Ehlers
M
Vollmer
P
Müllberg
J
Wolf
E
Brem
G
zum Büschenfelde K-HM
Rose-John
S
The function of the soluble interleukin 6 (IL-6) receptor in vivo: Sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6.
J Exp Med
183
1996
1399
296
Kishimoto
T
Akira
S
Narazaki
M
Taga
T
Interleukin-6 family of cytokines and gp130.
Blood
86
1995
1243
297
Ku
H
Hirayama
F
Kato
T
Miyazaki
H
Aritomi
M
Ota
Y
D'Andrea
AD
Lyman
SD
Ogawa
M
Soluble thrombopoietin receptor (Mpl) and granulocyte colony-stimulating factor receptor directly stimulate proliferation of primitive hematopoietic progenitors of mice in synergy with steel factor or the ligand for flt3/flk2.
Blood
88
1996
4124
298
Wells
A
Welsh
JB
Lazar
CS
Wiley
HS
Gill
GN
Rosenfeld
MG
Ligand-induced transformation by a noninternalizing epidermal growth factor receptor.
Science
247
1990
962
299
Wypych
J
Bennett
LG
Schwartz
MG
Clogston
CL
Lu
HS
Broudy
VC
Bartley
TD
Parker
VP
Langley
KE
Soluble Kit receptor in human serum.
Blood
85
1995
66
300
Liu
Y-C
Kawagishi
M
Kameda
R
Ohashi
H
Characterization of a fusion protein composed of the extracellular domain of c-kit and the Fc region of human IgG expressed in a baculovirus system.
Biochem Biophys Res Commun
197
1993
1094
301
Grichnik
JM
Crawford
J
Jimenez
F
Kurtzberg
J
Buchanan
M
Blackwell
S
Clark
RE
Hitchcock
MG
Human recombinant stem-cell factor induces melanocytic hyperplasia in susceptible patients.
J Am Acad Dermatol
33
1995
577
302
Moskowitz
CH
Stiff
P
Gordon
MS
McNiece
I
Ho
AD
Costa
JJ
Broun
ER
Bayer
RA
Wyres
M
Hill
J
Jelaca-Maxwell
K
Nichols
CR
Brown
SL
Nimer
SD
Gabrilove
J
Recombinant methionyl human stem cell factor and filgrastin for peripheral blood progenitor cell mobilization and transplantation in non-Hodgkin's lymphoma patients — Results of a phase I/II trial.
Blood
89
1997
3136
303
Tricot G, Jagannath S, Desikan KR, Siegel D, Munshi N, Olson E, Wyres M, Parker W, Barlogie B: Superior mobilization of peripheral blood progenitor cells (PBPC) with r-metHuSCF (SCF ) and r-metHuG-CSF (Filgrastim) in heavily pretreated multiple myeloma (MM) patients. Blood 88:388a, 1996 (abstr, suppl 1)
304
Nocka KH, Levine BA, Ko J-L, Burch PM, Landgraf BE, Segal R, Lobell R: Increased growth promoting but not mast cell degranulation potential of a covalent dimer of c-Kit ligand. Blood (in press)
305
Nocka KH, Burch P, Levine BA, Undem B, Segal R, Nair N, Alessi MK, Landgraf BE, Lobell R: Human c-kit ligand analogue, SAF-9, with increased growth factor but not mast cell stimulating activity. Blood 88:548a, 1996 (abstr, suppl 1)
306
Luskey
BD
Rosenblatt
M
Zsebo
K
Williams
DA
Stem cell factor, interleukin-3, and interleukin-6 promote retroviral-mediated gene transfer into murine hematopoietic stem cells.
Blood
80
1992
396
307
Williams
DA
Ex vivo expansion of hematopoietic stem and progenitor cells — Robbing Peter to pay Paul?
Blood
81
1993
3169
308
Emerson
SG
Ex vivo expansion of hematopoietic precursors, progenitors, and stem cells: The next generation of cellular therapeutics.
Blood
87
1996
3082
309
Ratajczak MZ, Pletcher C, Marliez W, Wasik M, Machalinski B, Ratajczak J, Moore J, Gewirtz AM: A rapid method for isolating human hematopoietic stem cells (HHSC). Blood 88:109a, 1996 (abstr, suppl 1)
310
Kasahara
N
Dozy
AM
Kan
YW
Tissue-specific targeting of retroviral vectors through ligand-receptor interactions.
Science
266
1994
1373
311
Schwarzenberger
P
Spence
SE
Gooya
JM
Michiel
D
Curiel
DT
Ruscetti
FW
Keller
JR
Targeted gene transfer to human hematopoietic progenitor cell lines through the c-kit receptor.
Blood
87
1996
472
312
Hsu
Y-R
Wu
G-M
Mendiaz
EA
Syed
R
Wypych
J
Toso
R
Mann
MB
Boone
TC
Narhi
LO
Lu
HS
Langley
KE
The majority of stem cell factor exists as monomer under physiological conditions.
J Biol Chem
272
1997
6406
313
Lemmon
MA
Pinchasi
D
Zhou
M
Lax
I
Schlessinger
J
Kit receptor dimerization is driven by bivalent binding of stem cell factor.
J Biol Chem
272
1997
6311