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Antiapoptotic Role of Growth Factors in the Myelodysplastic Syndromes: Concordance Between In vitro and In vivo Observations

Authors' Affiliations: ¹ Department of Medicine, Division of Hematology; ² Institute of Environmental Medicine, Division of Molecular Toxicology; ³ Institute of Environmental Medicine, Division of Toxicology; ⁴ Department of Laboratory Medicine, Division of Pathology, Karolinska University Hospital Huddinge; ⁵ Department of Medicine, Division of Hematology, Karolinska University Hospital Solna; ⁶ Department of Medicine, Southern Hospital, Karolinska Institutet, Stockholm, Sweden; and ⁷ Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota

Requests for reprints: Ramin Tehranchi, Department of Medicine, Division of Hematology, Karolinska University Hospital, Karolinska Institutet, Huddinge, S-141 86 Stockholm, Sweden. Phone: 46-8-58-58-3861; Fax: 46-8-58-58-3605; E-mail: Ramin.Tehranchi{at}medhs.ki.se.

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.

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