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Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and Β-Thalassemia

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Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and Β-Thalassemia International Journal of Molecular Sciences Review Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia Sarah Parisi 1,2,†, Carlo Finelli 1,2,†, Antonietta Fazio 3, Alessia De Stefano 3, Sara Mongiorgi 3, Stefano Ratti 3 , Alessandra Cappellini 3, Anna Maria Billi 3 , Lucio Cocco 3 , Matilde Y. Follo 3,* and Lucia Manzoli 3 1 Department of Oncology and Hematology, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; [email protected] (S.P.); carlo.fi[email protected] (C.F.) 2 Department of Experimental, Diagnostic and Specialty Medicine DIMES, Institute of Hematology “L. and A. Seràgnoli”, University of Bologna, 40138 Bologna, Italy 3 Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; [email protected] (A.F.); [email protected] (A.D.S.); [email protected] (S.M.); [email protected] (S.R.); [email protected] (A.C.); [email protected] (A.M.B.); [email protected] (L.C.); [email protected] (L.M.) * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Erythropoiesis regulation is essential in normal physiology and pathology, particularly in myelodysplastic syndromes (MDS) and β-thalassemia. Several signaling transduction processes, including those regulated by inositides, are implicated in erythropoiesis, and the latest MDS or β-thalassemia preclinical and clinical studies are now based on their regulation. Among others, the main pathways involved are those regulated by transforming growth factor (TGF)-β, which Citation: Parisi, S.; Finelli, C.; Fazio, negatively regulates erythrocyte differentiation and maturation, and erythropoietin (EPO), which A.; De Stefano, A.; Mongiorgi, S.; acts on the early-stage erythropoiesis. Also small mother against decapentaplegic (SMAD) signaling Ratti, S.; Cappellini, A.; Billi, A.M.; Cocco, L.; Follo, M.Y.; et al. Clinical molecules play a role in pathology, and activin receptor ligand traps are being investigated for future and Molecular Insights in clinical applications. Even inositide-dependent signaling, which is important in the regulation of cell Erythropoiesis Regulation of Signal proliferation and differentiation, is specifically associated with erythropoiesis, with phospholipase Transduction Pathways in C (PLC) and phosphatidylinositol 3-kinase (PI3K) as key players that are becoming increasingly Myelodysplastic Syndromes and important as new promising therapeutic targets. Additionally, Roxadustat, a new erythropoiesis β-Thalassemia. Int. J. Mol. Sci. 2021, stimulating agent targeting hypoxia inducible factor (HIF), is under clinical development. Here, we 22, 827. https://doi.org/10.3390/ review the role and function of the above-mentioned signaling pathways, and we describe the state ijms22020827 of the art and new perspectives of erythropoiesis regulation in MDS and β-thalassemia. Received: 21 December 2020 Keywords: erythropoiesis; signal transduction; myelodysplastic syndromes; β-thalassemia; inosi- Accepted: 13 January 2021 tides Published: 15 January 2021 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional clai- 1. Introduction ms in published maps and institutio- nal affiliations. Erythropoiesis is an essential process that is finely regulated. All stages are controlled by several molecules and several signal transduction pathways are implicated. For instance, the transforming growth factor (TGF)-β family negatively regulates the erythrocyte differ- entiation and maturation, whilst erythropoietin (EPO) is the main regulator of early-stage Copyright: © 2021 by the authors. Li- erythropoiesis. Ineffective erythropoiesis may cause anemia and is particularly relevant in censee MDPI, Basel, Switzerland. myelodysplastic syndromes (MDS) and in homozygous β-thalassemia, where small mother This article is an open access article against decapentaplegic (SMAD) signaling is altered and activin receptor ligand traps have distributed under the terms and con- been shown to correct the hyperactivation of SMAD2/3. New clinical approaches to coun- ditions of the Creative Commons At- teract anemia and support erythropoiesis are based on Roxadustat, a new erythropoiesis tribution (CC BY) license (https:// stimulating agent targeting hypoxia inducible factor (HIF). Finally, some data also hint at a creativecommons.org/licenses/by/ relevant role for phospholipase C and PI3K in erythropoiesis regulation. This review will 4.0/). Int. J. Mol. Sci. 2021, 22, 827. https://doi.org/10.3390/ijms22020827 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 15 Int. J. Mol. Sci. 2021, 22, 827 2 of 15 (HIF). Finally, some data also hint at a relevant role for phospholipase C and PI3K in focuserythropoiesis on these pathwaysregulation. and This describe review their will importancefocus on these in preclinical pathways studies and describe and clinical their applications,importance in because preclinical they studies are the and target clinical of new applications, therapeutic because agents which they are have the proved target toof benew highly therapeutic effective agents in improving which have anemia proved associated to be highly with effective MDS, β-thalassemia in improving and anemia chronic as- kidneysociated disease. with MDS, β-thalassemia and chronic kidney disease. 2. Targeting Transforming GrowthGrowth FactorFactor (TGF)-(TGF)-ββ SignalingSignaling toto ImproveImprove Erythropoie- Erythropoiesissis 2.1. Effective and Ineffective Erythropoiesis 2.1. Effective and Ineffective Erythropoiesis The process of erythropoiesis in humans is divided in two parts: the first is EPO- The process of erythropoiesis in humans is divided in two parts: the first is EPO- dependent and the second is iron-dependent (Figure1). Erythropoiesis occurs in ery- dependent and the second is iron-dependent (Figure 1). Erythropoiesis occurs in erythro- throblastic islands, anatomic niches composed of a central macrophage surrounded by blastic islands, anatomic niches composed of a central macrophage surrounded by erythroid cells at various stages of maturation: erythroid burst-forming units (BFU-E), erythroid cells at various stages of maturation: erythroid burst-forming units (BFU-E), erythroid colony-forming units (CFU-E), erythroid progenitors (proerythroblasts and ery- erythroid colony-forming units (CFU-E), erythroid progenitors (proerythroblasts and throblasts) [1]. erythroblasts) [1]. Figure 1.1. SchematicSchematic representation of erythroiderythroid developmentdevelopment and time-dependenttime-dependent expression of a complexcomplex networknetwork ofof transcriptiontranscription factorsfactors involvedinvolved in thethe process.process. EPO-dependent and iron-dependent stages of erythropoiesis are indicated. Differentiation, maturation, and proliferation of erythroid progenitorsprogenitors are regulatedregulated byby severalseveral moleculesmolecules accordingaccording toto different stages.stages. Stem cell factorfactor (SCF),(SCF), interleukin-3interleukin-3 (IL-3) and theirtheir receptorsreceptors progressivelyprogressively disappeardisappear duringduring erythroiderythroid maturation, after the Pro-E stage. GATA1 promotes erythropoiesis and increases the EPO receptor (EPO-R) expression, maturation, after the Pro-E stage. GATA1 promotes erythropoiesis and increases the EPO receptor (EPO-R) expression, which which is maintained until the Ortho-E stage. In turn, EPO is the main regulator of early-stage erythropoiesis, after the is maintained until the Ortho-E stage. In turn, EPO is the main regulator of early-stage erythropoiesis, after the BFU-E stage. BFU-E stage. Other molecules are regulators of iron metabolism, such as transferrin (Tf) and its cell receptor (Tfr), Othergrowth/differentiating molecules are regulators factor 11 of (GDF11) iron metabolism, and memb suchers as of transferrin the transforming (Tf) and itsgrowth cell receptor factor (TGF)- (Tfr), growth/differentiatingβ family, which nega- factortively 11regulate (GDF11) erythrocyte and members differentiation of the transforming and maturation growth from factor the (TGF)- earlyβ stagesfamily, (Tf/ whichTfr-1) negatively to the late regulate stages (Poly-E). erythrocyte Fi- differentiationnally, the binding and between maturation FAS from and theFAS early ligand stages (FASL) (Tf/Tfr-1) triggers to th thee apoptosis late stages of (Poly-E). immature Finally, erythroid the binding cells, acting between from FAS the andCFU-E FAS to ligand the Ortho-E (FASL) stages. triggers the apoptosis of immature erythroid cells, acting from the CFU-E to the Ortho-E stages. As depicted in Figure1 1,, proliferation, proliferation, differentiation,differentiation, andand maturation maturation ofof erythroid erythroid progenitors isis controlledcontrolled by by several several molecules molecules which which act act at at different different stages stages of erythropoiesis.of erythropoi- Stemesis. Stem cell factor cell factor (SCF) (SCF) and interleukinand interleukin 3 (IL-3) 3 (I targetL-3) target hematopoietic hematopoietic stem stem cells cells (HSC), (HSC), and theirand their receptors receptors gradually gradually disappear disappear during duri erythroidng erythroid maturation. maturation. GATA1 GATA1 promotes promotes ery- thropoiesiserythropoiesis during during several several stages, stages, because because it enhances it enhances
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