Granulocyte colony-stimulating factor inhibits Fas-triggered apoptosis in bone marrow cells isolated from patients with refractory anemia with ringedsideroblasts

Treatment with granulocyte colony-stimulating factor (G-CSF) plus erythropo ietin may synergistically improve hemoglobin levels and reduce bone marrow apoptosis in patients with refractory anemia with ringed sideroblasts (RARS ). Fas-induced caspase activity is increased in RARS bone marrow cells. We showed that G-CSF significantly reduced Fas-mediated caspase-8 and caspase- 3-like activity and the degree of nuclear apoptotic changes in bone marrow from nine RARS patients. A decrease in mitochondrial membrane potential and an increase in intracellular reactive oxygen species occurred in Fas-treat ed cells, but became significant only 24 h after changes in caspase activit y and decrease in proliferation. G-CSF also reduced the magnitude of these late apoptotic changes. In CD34-selected normal cells, G-CSF induced myeloi d colony growth, and an overall small decrease in the number of erythroid c olonies. By contrast, G-CSF induced a 33-263% increase of erythroid colony formation in CD34(+) cells from four of five RARS patients with severely re duced erythroid growth, while the normal or slightly reduced erythroid grow th of three other patients was not influenced by G-CSF. This study suggests that G-CSF may reduce the pathologically increased caspase activity and co ncomitant apoptotic changes, and promote erythroid growth and differentiati on of stem cells from RARS patients. Our data support the clinical benefit of G-CSF in this subgroup of myelodysplastic syndromes.