Antiapoptotic role of growth factors in the myelodysplastic syndromes: concordance between in vitro and in vivo observations.
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.
Tehranchi
Ramin
R
Department of Medicine, Division of Hematology, Karolinska University Hospital, Karolinska Institutet, Huddinge, Stockholm, Sweden. Ramin.Tehranchi@medhs.ki.se
Fadeel
Bengt
B
Schmidt-Mende
Jan
J
Forsblom
Ann-Mari
AM
Emanuelsson
Emma
E
Jadersten
Martin
M
Christensson
Birger
B
Hast
Robert
R
Howe
Robert B
RB
Samuelsson
Jan
J
Zhivotovsky
Boris
B
Hellström-Lindberg
Eva
E
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
D006021:Glycophorins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D045304:Cytochromes c; D020169:Caspases