The highly polymorphic human glucocorticoid receptor gene (GR) encodes the transcriptionally active GR? isoform similar to murine GR, GR?, an isoform with reduced transactivation potential and GR?, a dominant-negative isoform. Studies in human non-erythroid cells have identified that the pattern of GR isoform expression predicts cellular response to DXM in vitro. In addition, GR polymorphism is emerging as the leading cause for DXM unresponsiveness or for development of DXM resistance in patients with inflammatory and autoimmune diseases and in chronic depression. Clinical observations indicating that the GR ligand dexamethasone (DXM) stimulates erythropoiesis have been available since 1961. DXM is used as erythropoiesis stimulating agent (ESA) to rescue the deficient terminal erythroid (EB) maturation observed in patients with Diamond Blackfan Anemia (DBA), a congenic form of erythropoietin (EPO) resistant erythroid aplasia often associated with mutations that result in ribosome insufficiency. However the effects of the various GR isoforms on terminal erythroid maturation and whether these effects may determine DXM unresponsiveness in DBA patients (~50% of DBA patients do not respond to DXM) is still unknown. We recently identified that the rs6198 single nucleotide polymorphism (SNP) that stabilizes GRb mRNA is present with increased frequency in diseases of terminal EB maturation, associated with overproduction and erythrocytosis, as in polycythemia vera (55%) as well as underproduction (anemia) as in DBA (43%) (Varricchio et al, Blood 2011;218;425-436 and 473-474). These observations have generated a paradigm shift in our understanding of DXM as ESA highlighting the clinical need for additional studies on the effect of GR polymorphism on terminal EB maturation. We propose to characterize the biological activity of different GR isoforms in terminal EB maturation (Aim 1), to identify the microenvironmental and genetic factor(s) that regulate expression of these GR isoforms during terminal EB maturation (Aim 2) and to investigate the role exerted by individual GR isoforms in rescuing terminal EB maturation in DBA patients in vitro (Aim 3). We predict that these studies, by improving our understanding of the biology of GR in normal and DBA erythropoiesis, may identify more potent GR agonists (Aim 1) and pharmacological modulators (microenvironmental factors, Aim 2) to improve the treatment of DBA patients and possibly of other EPO resistant anemias.
The glucocorticoid receptor (GR) interacts with EPO-R signaling in switching terminal erythroid maturation from a steady-state to a stress mode. By understanding the role of individual GR isoforms in the induction of this switch, this proposal may greatly improve our understanding of the pathobiology of EPO resistant anemias, such as DBA, and contribute to the identification of alternative erythroid stimulating agents for their treatment.
|Migliaccio, Anna Rita (2016) To condition or not to condition-That is the question: The evolution ofÂ nonmyeloablative conditions for transplantation. Exp Hematol 44:706-12|
|Funnell, Alister P W; Prontera, Paolo; Ottaviani, Valentina et al. (2015) 2p15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment. Blood 126:89-93|
|Falchi, Mario; Varricchio, Lilian; Martelli, Fabrizio et al. (2015) Dexamethasone targeted directly to macrophages induces macrophage niches that promote erythroid expansion. Haematologica 100:178-87|
|Ciaffoni, Fiorella; Cassella, Elena; Varricchio, Lilian et al. (2015) Activation of non-canonical TGF-Î²1 signaling indicates an autoimmune mechanism for bone marrow fibrosis in primary myelofibrosis. Blood Cells Mol Dis 54:234-41|
|Paciaroni, Katia; Lucarelli, Guido; Martelli, Fabrizio et al. (2014) Transfusion-independent Î²(0)-thalassemia after bone marrow transplantation failure: proposed involvement of high parental HbF and an epigenetic mechanism. Am J Blood Res 4:27-32|
|Masiello, Francesca; Tirelli, Valentina; Sanchez, Massimo et al. (2014) Mononuclear cells from a rare blood donor, after freezing under good manufacturing practice conditions, generate red blood cells that recapitulate the rare blood phenotype. Transfusion 54:1059-70|
|Revelli, Nicoletta; Villa, Maria Antonietta; Paccapelo, Cinzia et al. (2014) The Lombardy Rare Donor Programme. Blood Transfus 12 Suppl 1:s249-55|
|Varricchio, Lilian; Dell'Aversana, Carmela; Nebbioso, Angela et al. (2014) Identification of NuRSERY, a new functional HDAC complex composed by HDAC5, GATA1, EKLF and pERK present in human erythroid cells. Int J Biochem Cell Biol 50:112-22|
|Migliaccio, A R (2013) Stem cell-derived erythrocytes as upcoming players in blood transfusion. ISBT Sci Ser 8:165-171|
|Zingariello, Maria; Martelli, Fabrizio; Ciaffoni, Fiorella et al. (2013) Characterization of the TGF-Î²1 signaling abnormalities in the Gata1low mouse model of myelofibrosis. Blood 121:3345-63|
Showing the most recent 10 out of 18 publications