0000000000393345
AUTHOR
Emilie Frisan
Role of GATA-1 and HSP70 in the Dyserythropoiesis of Early Myelodysplastic Syndromes.
Abstract Abstract 3823 Poster Board III-759 Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem cell disorders characterized by a hypercellular dysplastic bone marrow (BM) with peripheral blood cytopenias, mainly anemia. Early MDS with less than 10% BM blasts which belong in most cases to low and intermediate-1 (int-1) risk groups according to the International Prognostic Scoring System (IPSS), usually demonstrate dyserythropoiesis. The growth of erythroid progenitors is altered, with increased caspase activation leading to excessive cell death, and cellular dysplasia characterized, in liquid culture of CD34+-derived erythroid progenitors, by a delayed expression of the gly…
Heat shock proteins: essential proteins for apoptosis regulation
Abstract Many different external and intrinsic apoptotic stimuli induce the accumulation in the cells of a set of proteins known as stress or heat shock proteins (HSPs). HSPs are conserved proteins present in both prokaryotes and eukaryotes. These proteins play an essential role as molecular chaperones by assisting the correct folding of nascent and stress-accumulated misfolded proteins, and by preventing their aggregation. HSPs have a protective function, that is they allow the cells to survive to otherwise lethal conditions. Various mechanisms have been proposed to account for the cytoprotective functions of HSPs. Several of these proteins have demonstrated to directly interact with compo…
Defective nuclear localization of Hsp70 is associated with dyserythropoiesis and GATA-1 cleavage in myelodysplastic syndromes.
Abstract Normal human erythroid cell maturation requests the transcription factor GATA-1 and a transient activation of caspase-3, with GATA-1 being protected from caspase-3–mediated cleavage by interaction with the chaperone heat shock protein 70 (Hsp70) in the nucleus. Erythroid cell dysplasia observed in early myelodysplastic syndromes (MDS) involves impairment of differentiation and excess of apoptosis with a burst of caspase activation. Analysis of gene expression in MDS erythroblasts obtained by ex vivo cultures demonstrates the down-regulation of a set of GATA-1 transcriptional target genes, including GYPA that encodes glycophorin A (GPA), and the up-regulation of members of the HSP70…
Spontaneous and Fas-induced apoptosis of low-grade MDS erythroid precursors involves the endoplasmic reticulum
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 cytochrom…