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Myelodysplasias

Spontaneous and Fas-induced apoptosis of low-grade MDS erythroid precursors involves the endoplasmic reticulum

Abstract

Spontaneous apoptosis of bone marrow erythroid precursors accounts for the anemia that characterizes most low-grade myelodysplastic syndromes (MDS). We have shown that death of these precursors involved the Fas-dependent activation of caspase-8. To explore the pathway leading from caspase-8 activation to apoptosis, we transduced MDS bone marrow CD34+ cells with a lentivirus encoding wild-type (WT) or endoplasmic reticulum (ER)-targeted Bcl-2 protein before inducing their erythroid differentiation. Both WT-Bcl-2 and ER-targeted Bcl-2 prevented spontaneous and Fas-dependent apoptosis in MDS erythroid precursors. ER-targeted Bcl-2 inhibited mitochondrial membrane depolarization and cytochrome c release in MDS erythroid precursors undergoing apoptosis, indicating a role for the ER in the death pathway, upstream of the mitochondria. MDS erythroid precursors demonstrated elevated ER Ca2+ stores and these stores remained unaffected by ER-targeted Bcl-2. The ER-associated protein Bcl-2-associated protein (BAP) 31 was cleaved by caspase-8 in MDS erythroid precursors undergoing apoptosis. The protective effect of ER-targeted Bcl-2 toward spontaneous and Fas-induced apoptosis correlated with inhibition of BAP31 cleavage. A protective effect of erythropoietin against Fas-induced BAP31 cleavage and apoptosis was observed. We propose that apoptosis of MDS erythroid precursors involves the ER, downstream of Fas and upstream of the mitochondria, through the cleavage of the ER-associated BAP31 protein.

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Acknowledgements

We thank Dr GC Shore for providing tools, Dr G Szabadkai and Dr B Papp for helpful discussions. This study was supported by grants from the Direction regionale de la Recherche Clinique, AP-HP (MUL03009), and from the Canceropole Ile-de-France. EG was the recipient of a fellowship from Inserm (poste d’accueil) and from the Fondation de France—Fondation contre la Leucémie. PM and ES groups were supported by the Ligue Nationale Contre le Cancer. EG, EF, J-CD and CP-E performed research study and analyzed data; OB-R, FD and ES recorded patients, CR, AD-K and CG reviewed the paper and contributed analytic tools; CL and PM analyzed data; ES and MF analyzed data and wrote the paper.

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Correspondence to M Fontenay.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Gyan, E., Frisan, E., Beyne-Rauzy, O. et al. Spontaneous and Fas-induced apoptosis of low-grade MDS erythroid precursors involves the endoplasmic reticulum. Leukemia 22, 1864–1873 (2008). https://doi.org/10.1038/leu.2008.172

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