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

Abstract

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.

Is there a role for all-trans retinoic acid in combination with recombinant erythropoetin in myelodysplastic syndromes? A report on 59 cases

“…This model is in line with previous in vitro findings 34 and may be similar to that described with G-CSF, 35 as those two drugs appear to share common in vitro properties in MDS cell lines. 36 It would therefore be of interest to compare the efficacy of r-EPO-ATRA and r-EPO-G-CSF combinations.…”

Lenalidomide inhibits the malignant clone and up-regulates theSPARCgene mapping to the commonly deleted region in 5q− syndrome patients

“…The standard antibody panel included markers of early and late erythroid [CD36 and glycophorin-A (GPA), respectively], and myeloid (CD33) differentiation. At day 7, the CD34 ϩ progenitors had differentiated into intermediate erythroblasts, as previously described (32,34), and the lenalidomide-treated cells showed a phenotype similar to that of the untreated cells ( Fig. 1 D and F).…”

“…Next, we evaluated the specific effect of lenalidomide during days 0-14. By correlating the proliferation index to the proportion of 5q31-deleted cells as determined by FISH, we could estimate the proliferation of the normal cells and the malignant clone independently, as previously described (32).…”

Mitochondria in hematopoiesis and hematological diseases

“…The erythroid apoptosis that characterizes myelodysplastic syndromes could be inhibited by growth factors such as Epo (Tehranchi et al, 2005). The question remains opened of whether strategies aiming to inhibit cell death in early-stage myelodysplastic syndromes could favor accumulation of blast cells and transformation.…”