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RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway

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RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway International Journal of Molecular Sciences Article RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway Gianluca De Rosa 1,2 , Immacolata Andolfo 1,2,*, Roberta Marra 1,2, Francesco Manna 2, Barbara Eleni Rosato 1,2, Achille Iolascon 1,2 and Roberta Russo 1,2,* 1 Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy; [email protected] (G.D.R.); [email protected] (R.M.); [email protected] (B.E.R.); [email protected] (A.I.) 2 Ceinge Biotecnologie Avanzate, 80145 Naples, Italy; [email protected] * Correspondence: [email protected] (I.A.); [email protected] (R.R.); Tel.: +39-081-3737736 (I.A.); +39-081-3737736 (R.R.) Received: 9 July 2020; Accepted: 30 July 2020; Published: 4 August 2020 Abstract: Congenital dyserythropoietic anemia type II (CDA II) is a hypo-productive anemia defined by ineffective erythropoiesis through maturation arrest of erythroid precursors. CDA II is an autosomal recessive disorder due to loss-of-function mutations in SEC23B. Currently, management of patients with CDA II is based on transfusions, splenectomy, or hematopoietic stem-cell transplantation. Several studies have highlighted benefits of ACE-011 (sotatercept) treatment of ineffective erythropoiesis, which acts as a ligand trap against growth differentiation factor (GDF)11. Herein, we show that GDF11 levels are increased in CDA II, which suggests sotatercept as a targeted therapy for treatment of these patients. Treatment of stable clones of SEC23B-silenced erythroleukemia K562 cells with the iron-containing porphyrin hemin plus GDF11 increased expression of pSMAD2 and reduced nuclear localization of the transcription factor GATA1, with subsequent reduced gene expression of erythroid differentiation markers. We demonstrate that treatment of these SEC23B-silenced K562 cells with RAP-011, a “murinized” ortholog of sotatercept, rescues the disease phenotype by restoring gene expression of erythroid markers through inhibition of the phosphorylated SMAD2 pathway. Our data also demonstrate the effect of RAP-011 treatment in reducing the expression of erythroferrone in vitro, thus suggesting a possible beneficial role of the use of sotatercept in the management of iron overload in patients with CDA II. Keywords: congenital dyserythropoietic anemia type II; activin receptor II ligand trap; in vitro drug treatment 1. Introduction Congenital dyserythropoietic anemias (CDAs) are a group of rare hereditary disorders that are defined by maturation arrest of the erythroid lineage, the main consequence of which is ineffective erythropoiesis, with the consequent reduced production of erythrocytes [1]. CDA type II (CDA II) is the most common form of CDAs, and it is caused by biallelic loss-of-function mutations in the SEC23B gene. SEC23B encodes a protein of the COPII complex that is involved in intracellular vesicle trafficking from the endoplasmic reticulum to the Golgi compartment [2,3]. CDA II is characterized by normocytic anemia of variable degree and relative reticulocytopenia, which are often accompanied by jaundice and splenomegaly, due to the hemolytic component. Bone-marrow examination of patients with CDA II has highlighted erythroid hyperplasia and the presence of bi-nucleated and multi-nucleated erythroblasts, due to maturation arrest [1,4]. The most harmful complication for patients with CDA II Int. J. Mol. Sci. 2020, 21, 5577; doi:10.3390/ijms21155577 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 5577 2 of 11 De Rosa G et al. 2 of 11 is iron overload [5]. Indeed, ineffective erythropoiesis results in strong downregulation of the hepatic ironhormone absorption hepcidin, and and systemic this condition iron canoverload lead to, increasedwhich is iron mediated absorption byand the systemic erythroid iron hormone overload, erythroferronewhich is mediated (ERFE) by the[6]. erythroid hormone erythroferrone (ERFE) [6]. InIn the the last last years, years, members members of of the the tr transformingansforming growth growth factor-beta factor-beta (TGF- (TGF-ββ)) superfamily, superfamily, which which includesincludes activins activins (A (A and and B), B), grow growthth differentiation differentiation factors factors (GDFs) (GDFs) and and bone bone morphogenetic morphogenetic proteins proteins (BMPs),(BMPs), have have been been studied studied as as potential potential regulators regulators of of erythropoiesis. erythropoiesis. In In particular, particular, GDF11 GDF11 (also (also known known asas BMP11) BMP11) has been investigatedinvestigated asas aa possiblepossible negative negative regulator regulator of of erythropoiesis. erythropoiesis. Indeed, Indeed, through through its itsbinding binding to activinto activin receptors receptors (ActR) (ActR) IIA IIA and and IIB, IIB, GDF11 GDF11 can can inhibit inhibit terminal terminal erythroid erythroid maturation maturation [7]. [7].Nevertheless, Nevertheless, arecent a recent study study excluded excluded that thatGDF11 GDF11 isis the only only effector effector of of TGF- TGF- inhibitioninhibition of lat latee erythropoiesiserythropoiesis in in mice, mice, but but it it may may contribute contribute toge togetherther with with other other related related cytokines cytokines to to ineffective ineffective erythropoiesiserythropoiesis [8]. [8]. ToTo date, date, treatments treatments for for patients patients with with CDA CDA II IIha haveve only only included included supportive supportive therapies, therapies, such such as transfusion,as transfusion, splenectomy splenectomy and and hematopoietic hematopoietic stem stem-cell-cell transplantation transplantation in in transfusion-dependent patientspatients [1,4,9,10]. [1,4,9,10]. Of Of note, note, two two inhibitors inhibitors of TGF- of TGF- pathway, pathway, ACE-011ACE-011 (sotatercept)(sotatercept) and ACE-536 ACE-536 (luspatercept),(luspatercept), areare ligand ligand traps traps for for ActRIIA ActRIIA and ActRIIB,and ActRIIB, respectively, respectively, and their and use their has beenuse associatedhas been associatedwith improved with improved hematologic hematologic parameters parameters in healthy in healthy post-menopausal post-menopausal women women [11]. Studies[11]. Studies with withthe “murinized” the “murinized” orthologs orthologs of sotatercept of sotatercept and luspatercept, and luspatercept, known as known RAP-011 as and RAP-011 RAP-536, and respectively, RAP-536, respectively,in a murine modelin a murine of β-thalassemia model of β resulted-thalassemia in increased resulted di infferentiation increased ofdifferentiation erythroid cells, of erythroid improved cells,anemia improved and reduced anemia iron and overload reduced in the iron treated overload mice [in11 ,the12]. treated Sotatercept mice and [11,12]. its murinized Sotatercept counterpart and its murinizedRAP-011 are counterpart chimeric proteins RAP-011 where are chimeric the extracellular proteins where domain the of extracellular the ActRIIA receptordomain of has the been ActRIIA fused receptorto the Fc has portion been fused of the to human the Fc (orportion mouse, of the respectively) human (or IgG1mouse, antibody respective [13ly)]. IgG1 RAP-011 antibody treatment [13]. RAP-011has already treatment been evaluated has already in abeenβ-thalassemia evaluated murinein a β-thalassemia model, as wellmurine as inmodel, a zebrafish as well model as in ofa zebrafishDiamond–Blackfan model of Diamond anemia [–7Blackfan,13]. anemia [7,13]. Here,Here, we we investigated investigated the the effects effects of ofRAP-011 RAP-011 treatment treatment in an in in an vitroin vitro CDACDA II model II model of the of erythroleukemiathe erythroleukemia K562 K562 cell line cell linestably stably silenced silenced for SEC23B for SEC23B expression.expression. 2.2. Results Results 2.1.2.1. Ex Ex Vivo Vivo and InIn VitroVitro Quantitative Quantitative Evaluation Evaluation of GDF11 of GDF11 OnOn the the basis basis of of data data that that corre correlatelate increased increased GDF11 GDF11 levels levels to β to-thalassemia,β-thalassemia, we investigated we investigated the expressionthe expression of this of thiscytokine cytokine in healthy in healthy controls controls and and patients patients with with CDA CDA II. II. In In total, total, 15 15 healthy healthy controls controls andand 12 12 patients patients with with SEC23BSEC23B-related-related CDA CDA II II provided provided peripheral peripheral blood blood for for evaluation evaluation of of protein protein expressionexpression of GDF11. The ex vivo analysisanalysis atat thethe proteinprotein level level showed showed 2.2-fold 2.2-fold increased increased expression expression of ofsecreted secreted GDF11 GDF11 in in plasma plasma samples samples from from the the patients patients with with CDACDA IIII comparedcompared to the healthy controls controls (Figure(Figure 11a,b).a,b). Figure 1. Ex vivo analysis of GDF11 expression. (a) Densitometry quantification of GDF11 expression Figurein plasma 1. Ex samples vivo analysis from of healthy GDF11 controls expression. (HCs; (a)n Densitometry= 15) and patients quantification with CDA of GDF11 II (n = expression12) on red ponceau-stained membrane. O.D., optical density. Data are means standard error. p-value by in plasma samples from healthy controls (HCs; n = 15) and patients ±with CDA II (n = 12) on red ponceau-stainedMann–Whitney tests.membrane. (b) Representative O.D., optical Westerndensity. Data blot forare GDF11means
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