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

Abstract

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). Fasinduced caspase activity is increased in RARS bone marrow cells. We showed that G-CSF significantly reduced Fasmediated 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. Leukemia (2001) 15, 742-751.

Antiapoptotic Role of Growth Factors in the Myelodysplastic Syndromes: Concordance Between In vitro and In vivo Observations

“…Bone marrow needle aspiration and mononuclear cell isolation and cultivation were done as previously described (16,17). Mononuclear cells were cultured in medium alone or in the presence of agonistic antiFas antibodies (1 Ag/mL; clone CH-11; Medical & Biological Laboratories Ltd., Nagoya, Japan) and/or G-CSF (100 ng/mL; Neupogen, Amgen, Twelve Oaks, CA) for the indicated time points.…”

Apoptotic mechanisms in the control of erythropoiesis

“…Interestingly, Fas-triggered apoptosis in bone marrow cells of MDS patients with refractory anemia with ringed sideroblasts is significantly improved by G-CSF treatment; particularly, the addition of G-CSF to CD34 þ cells improves erythroid colony formation in these patients. 164 As mentioned above, patients with more advanced stages of the MDS disease and with poor prognosis due to the presence of cytogenetic abnormalities may exhibit a condition different from that reported in MDS patients with refractory anemia (RA) or RA with ringed sideroblasts. In fact, some of these patients may exhibit an increased resistance to apoptosis instead of an increased sensitivity.…”

Early mitochondrial alterations in ATRA-induced cell death

“…[19][20][21] We have earlier shown that G-CSF decreases cytochrome c release from mitochondria to cytosol, thereby reducing caspase activation and premature death of cultured MDS erythroblasts. 22,23 However, the precise mode of the antiapoptotic action of G-CSF is still unclear.…”