In response to EPO, DNA synthesis, GATA-1 binding activity, and signal transducer and activator of transcription (STAT)5 activation were found to be absent or severely decreased in MDS compared with normal marrow cells (13); however, another study determined that ineffective erythropoiesis was more strongly correlated with stimulation of Fas-mediated proapoptotic pathways than with defective antiapoptotic signaling by the JAK2-STAT5 pathway (103). In some cases, both mechanisms appear to be operative. Apoptosis is associated with increased Fas ligand production during the stage of erythroid differentiation stage, a process that can be inhibited by a chimeric
Fas-Fc protein (104). Using both morphology and fluorescent in situ hybridization (FISH) in cytogenetically categorized patients with MDS, rHuEPO treatment in responding patients resulted in a significantly lower proportion of FISH-abnormal ery-throid precursors compared with before rHuEPO treatment (105). In addition, patients responding to rHuEPO had a significantly lower percentage of FISH abnormal ery-throid precursors compared with unresponsive individuals. The results are consistent with rHuEPO-induced proliferation of residual karyotypically normal erythroid precursors in MDS marrows.
Studies of apoptosis within MDS marrow progenitor cells have begun to unravel the mechanism whereby rHuG-CSF synergistically works with rHuEPO to improve the Hb concentration in patients with MDS. In the RARS subgroup, rHuG-CSF inhibited the increased Fas-induced apoptosis of MDS bone marrow cells (106). rHuG-CSF mediated reductions in caspase-8 and caspase-3-like activity, with concomitant reductions in the amount of late cellular apoptotic changes. Erythroid progenitor cells from patients with MDS also spontaneously released cytochrome c from mitochondria, with subsequent activation of caspase-9, an additional apoptotic pathway that can be inhibited by rHuG-CSF (107). Among low-risk MDS patients studied, this effect was most pronounced in erythroid progenitors from RARS patients.
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