Treatment with
granulocyte colony-stimulating factor (
G-CSF) plus
erythropoietin 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-treated cells, but became significant only 24 h after changes in
caspase activity and decrease in proliferation.
G-CSF also reduced the magnitude of these late apoptotic changes. In CD34-selected normal cells,
G-CSF induced myeloid colony growth, and an overall small decrease in the number of erythroid colonies. By contrast,
G-CSF induced a 33-263% increase of erythroid colony formation in CD34+ cells from four of five RARS patients with severely reduced erythroid growth, while the normal or slightly reduced erythroid growth of three other patients was not influenced by
G-CSF. This study suggests that
G-CSF may reduce the pathologically increased
caspase activity and concomitant apoptotic changes, and promote erythroid growth and differentiation of stem cells from RARS patients. Our data support the clinical benefit of
G-CSF in this subgroup of
myelodysplastic syndromes.