title: Antiapoptotic role of growth factors in the myelodysplastic syndromes: concordance between in vitro and in vivo observations.
abstract: OBJECTIVE
  Erythroid apoptosis in low-risk myelodysplastic syndrome (MDS) maybe mediated via mitochondrial release of cytochrome c and subsequent caspase activation. In the present study, we compared the in vitro and in vivo effects of proerythroid treatment with erythropoietin + granulocyte colony-stimulating factor (G-CSF) on myelodysplastic erythropoiesis regarding apoptosis and preferential growth of clones with cytogenetic abnormalities.
  
  
  METHODS
  We enrolled 15 refractory anemia (RA) and 11 refractory anemia with ringed sideroblasts (RARS), including 5q- aberration, monosomy 7, and trisomy 8, before initiation of treatment and followed nine patients after successful treatment. The effects of G-CSF and erythropoietin were assessed. The expression of G-CSF receptor (G-CSFR) was explored during erythroid maturation. The relative growth of erythroid progenitors with cytogenetic aberrations in presence of erythropoietin was investigated.
  
  
  RESULTS
  Significant redistribution of cytochrome c was seen before treatment at all stages of erythroid differentiation. This release was blocked by G-CSF during the whole culture period and by erythropoietin during the latter phase. Both freshly isolated glycophorin A+ bone marrow cells and intermediate erythroblasts during cultivation retained their expression of G-CSFR. Cytochrome c release and caspase activation were significantly less pronounced in progenitors obtained from successfully treated nonanemic patients and showed no further response to G-CSF in vitro. Moreover, erythropoietin significantly promoted growth of cytogenetically normal cells from 5q- patients, whereas no such effect was observed on erythroblasts from monosomy 7 or trisomy 8 patients.
  
  
  CONCLUSIONS
  We conclude that growth factors such as erythropoietin and G-CSF can act both via inhibition of apoptosis of myelodysplastic erythroid precursors and via selection of cytogenetically normal progenitors.
authors.affiliation: Department of Medicine, Division of Hematology, Karolinska University Hospital, Karolinska Institutet, Huddinge, Stockholm, Sweden. Ramin.Tehranchi@medhs.ki.se
authors.forename: Ramin
authors.initials: R
authors.lastname: Tehranchi
authors.forename: Bengt
authors.initials: B
authors.lastname: Fadeel
authors.forename: Jan
authors.initials: J
authors.lastname: Schmidt-Mende
authors.forename: Ann-Mari
authors.initials: AM
authors.lastname: Forsblom
authors.forename: Emma
authors.initials: E
authors.lastname: Emanuelsson
authors.forename: Martin
authors.initials: M
authors.lastname: Jadersten
authors.forename: Birger
authors.initials: B
authors.lastname: Christensson
authors.forename: Robert
authors.initials: R
authors.lastname: Hast
authors.forename: Robert B
authors.initials: RB
authors.lastname: Howe
authors.forename: Jan
authors.initials: J
authors.lastname: Samuelsson
authors.forename: Boris
authors.initials: B
authors.lastname: Zhivotovsky
authors.forename: Eva
authors.initials: E
authors.lastname: Hellström-Lindberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000753:Anemia, Refractory / Q000188:drug therapy* / Q000473:pathology; D000756:Anemia, Sideroblastic / Q000188:drug therapy* / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015672:Erythroid Precursor Cells / Q000187:drug effects* / Q000473:pathology; D004921:Erythropoietin / Q000494:pharmacology; D006021:Glycophorins / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008875:Middle Aged; D009006:Monosomy; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D011994:Recombinant Proteins; D014314:Trisomy
chemical_list: D006021:Glycophorins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D045304:Cytochromes c; D020169:Caspases