Stem cell factor as a survival and growth factor in human normal and malignant hematopoiesis.
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-beta and interleukin-4, decreased c-kit expression, whereas tumor necrosis factor-alpha increased c-kit expression, but chemotherapeutic drugs showed no effect on 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-pit expression combined with chemotherapy offers potential for designing novel therapeutic approaches for refractory AML patients.
Hassan
H T
HT
Department of Hematology and Oncology, Hamburg University Hospital Eppendorf, Germany.
Zander
A
A
D000208:Acute Disease; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology; D006402:Hematologic Diseases / Q000473:pathology*; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D019089:Stem Cell Factor / Q000494:pharmacology / Q000502:physiology*
D016207:Cytokines; D006133:Growth Substances; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit