Stem Cell Factor as a Survival and Growth Factor in Human Normal and Malignant Hematopoiesis

Abstract

Stem cell factor (SCF) is an essential hematopoietic cytokine that interacts with other cytokines to preserve the viability of hematopoietic stem and progenitor cells, to influence their entry into the cell cycle and to facilitate their proliferation and differentiation. SCF on its own cannot drive noncycling hematopoietic progenitor cells into the cell cycle but does prevent their apoptotic death. SCF when combined with other cytokines increases the cloning efficacy of hematopoietic progenitor cells from all lineages. SCF also stimulates the growth of CD34+ leukemic progenitor cells from most patients with acute myeloid leukemia (AML). The mRNA expression of the SCF receptor c-kit has been shown to be significantly increased in all fresh AML blast cells compared with normal controls (healthy volunteers), in particular CD34+ cells. Two inhibitory cytokines, transforming growth factor-β and interleukin-4, decreased c-kit expression, whereas tumor necrosis factor-α increased c-kit expression, but chemotherapeutic drugs showed no effect on c-kit expression in AML cells. Apoptosis has been shown to be directly related to a high complete remission rate in AML patients following induction therapy. Since SCF has been shown to stimulate the proliferation of mainly CD34+ AML cells, we have investigated whether the poor response of patients with CD34+ myeloid leukemia cells to chemotherapy could be due to SCF-induced resistance to apoptosis. The effect of SCF on the apoptosis induced by chemotherapeutic drugs commonly used in the treatment of AML – cytarabine, daunorubicin and carboplatin – was examined in human CD34+ myeloid leukemia cells in serum-free cultures. SCF significantly reduced the induced apoptosis by more than 50% in all CD34+ human leukemia cells treated by any of the three chemotherapeutic drugs. Antibodies blocking c-kit reversed the significant inhibitory effect of SCF on chemotherapy-induced apoptosis, confirming the role of SCF in the resistance to chemotherapy-induced apoptosis in CD34+ human leukemia. These results suggest that the poor response of patients with CD34+ leukemia cells could be at least partially due to less chemotherapy-induced apoptosis resulting from protection by SCF as an adjuvant mechanism for drug resistance in myeloid leukemia. We conclude that an antisense strategy to block c-kit expression in AML blast cells may prove valuable for decreasing the chemoresistance of AML patients. The abrogation of leukemic resistance to apoptotic death through anti-SCF/c-kit expression combined with chemotherapy offers potential for designing novel therapeutic approaches for refractory AML patients.

Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington's disease

“…6A and B, SCF triggered the activation of c-kit in both cell types, as demonstrated by an increase in the phospho-c-kit signal, and this consequently resulted in the phosphorylation of Erk. The SCF-c-kit pathway is well known as a promoter of migration in different types of stem cells such as hematopoietic (Hassan and Zander, 1996 for review), spermatogonial (Ohta et al, 2003) and neural stem cells (Jin et al, 2002;Erlandsson et al, 2004;Sun et al, 2004). We therefore examined the possibility that the activation of the c-kit pathway led to a similar functional effect, in addition to the increased kinase activity detected biochemically.…”

Sequential analysis of CD34+ and CD34− cell subsets in peripheral blood and leukapheresis products from breast cancer patients mobilized with SCF plus G-CSF and cyclophosphamide

“…Accordingly, SCF has been shown to promote proliferation and differentiation of early progenitor cells, as well as to increase their survival, while at the same time exerting its effects on mature mast cells from different tissues. 14,15 Previous studies have shown that once administered in combination with other cytokines such as G-CSF, SCF has a synergistic effect on enhancing mobilization of CD34 ϩ HPCs into the PB. 16 Accordingly, accumulating evidence exists that the combined use of G-CSF and SCF is associated with higher mobilization rates as compared to G-CSF alone.…”

“…[17][18][19] Moreover, SCF has become an alternative agent in patients who show a poor response to other mobilization protocols. Although the biological and clinical effects of SCF administration have been extensively explored, 14,20 information is still scanty on the impact of administration of SCF combined with other cytokines and/or chemotherapy on the relative composition of both the CD34 ϩ and CD34 Ϫ cell subsets some of which have a potentially important role in predicting the outcome of either autologous or allogeneic transplants; these include the subsets of more immature CD34 ϩ HPC and DC, among others. 21,22 The aim of the present study was to gain further insights into the effects of the use of SCF in combination with G-CSF and cyclophosphamide.…”

Cytokine‐Induced Expansion of Human CD34+Stem/Progenitor and CD34+CD41+Early Megakaryocytic Marrow Cells Cultured on Normal Osteoblasts

“…Human bone marrow stroma is responsible for supporting both the daily production of billions of mature blood cells [1] and the generation of osteoblasts [2,3], the major contributor to bone formation from CD34 + marrow stem/progenitor cells [4,5]. Ultrastructural and developmental studies have also demonstrated the close physical association between endosteal osteoblasts and hemopoietic marrow cells in the bone marrow (BM) cavity [6][7][8].…”

“…Moreover, normal human osteoblasts produce several hemopoietic cytokines, including G-CSF [9], macrophage colony-stimulating factor (M-CSF) [10], interleukin 6 (IL-6) [11], tumor necrosis factor-alpha (TNF-α) [12], leukemia inhibitory factor (LIF) [13] and osteoclast differentiation factor (ODF) [14] as well as GM-CSF and IL-8 upon IL-1 stimulation [15]. These cytokines are required for both hemopoiesis [1] and the generation of osteoclasts for bone modulation from peripheral blood [14,16,17], cord blood [18], and BM [19] cells. Also, allogeneic transplantation of a donor-derived bone graft along with BM stem/progenitor cells in mice has promoted complete hemopoietic reconstitution and improved immune reconstitution after transplants in a chimeric-resistant combination [20][21][22][23], indicating a clear facilitating role for osteoblasts in allogeneic bone marrow transplantation (BMT).…”