Antiapoptotic role of growth factors in the myelodysplastic syndromes: concordance between in vitro and in vivo observations

Clin Cancer Res. 2005 Sep 1;11(17):6291-9. doi: 10.1158/1078-0432.CCR-04-1850.


Purpose: 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.

Experimental design: 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.

Conclusion: 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anemia, Refractory / drug therapy*
  • Anemia, Refractory / pathology
  • Anemia, Sideroblastic / drug therapy*
  • Anemia, Sideroblastic / pathology
  • Apoptosis / drug effects*
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Caspases / metabolism
  • Cytochromes c / metabolism
  • Enzyme Activation / drug effects
  • Erythroid Precursor Cells / drug effects*
  • Erythroid Precursor Cells / pathology
  • Erythropoietin / pharmacology
  • Glycophorins / metabolism
  • Granulocyte Colony-Stimulating Factor / pharmacology
  • Humans
  • In Vitro Techniques
  • Middle Aged
  • Monosomy
  • Receptors, Granulocyte Colony-Stimulating Factor / metabolism
  • Recombinant Proteins
  • Trisomy


  • Glycophorins
  • Receptors, Granulocyte Colony-Stimulating Factor
  • Recombinant Proteins
  • Erythropoietin
  • Granulocyte Colony-Stimulating Factor
  • Cytochromes c
  • Caspases