Granulocyte colony-stimulating factor inhibits spontaneous cytochrome c release and mitochondria-dependent apoptosis of myelodysplastic syndrome hematopoietic progenitors.
Low-risk myelodysplastic syndromes (MDS), including refractory anemia and sideroblastic anemia, are characterized by increased apoptotic death of erythroid progenitors. The signaling pathways that elicit this pathologic cell death in MDS have, however, remained unclear. Treatment with erythropoietin in combination with granulocyte colony-stimulating factor (G-CSF) may synergistically improve the anemia in patients with MDS, with a concomitant decrease in the number of apoptotic bone marrow precursors. Moreover, we have previously reported that G-CSF inhibits Fas-induced caspase activation in sideroblastic anemia (RARS). The present data demonstrate that almost 50% of erythroid progenitor cells derived from patients with MDS exhibit spontaneous release of cytochrome c from mitochondria with ensuing activation of caspase-9, whereas normal erythroid progenitors display neither of these features. G-CSF significantly inhibited cytochrome c release and suppressed apoptosis, most noticeably in cells from patients with sideroblastic anemia. Furthermore, inhibition of caspase-9 suppressed both spontaneous and Fas-mediated apoptosis of erythroid progenitors in all low-risk MDS cases studied. We propose that the increased sensitivity of MDS progenitor cells to death receptor stimulation is due to a constitutive activation of the mitochondrial axis of the apoptotic signaling pathway in these cells. These studies yield a mechanistic explanation for the beneficial clinical effects of growth factor administration in patients with MDS, and provide a model for the study of growth factor-mediated suppression of apoptosis in other bone marrow disorders.
Tehranchi
Ramin
R
Department of Medicine, Division of Hematology, Huddinge University Hospital, Stockholm, Sweden.
Fadeel
Bengt
B
Forsblom
Ann-Mari
AM
Christensson
Birger
B
Samuelsson
Jan
J
Zhivotovsky
Boris
B
Hellstrom-Lindberg
Eva
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D016022:Case-Control Studies; D061945:Caspase Inhibitors; D003574:Cytochrome c Group / Q000187:drug effects / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000473:pathology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D009190:Myelodysplastic Syndromes / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D019014:fas Receptor / Q000494:pharmacology
D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D019014:fas Receptor; D016179:Granulocyte Colony-Stimulating Factor