RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway
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 <i>SEC23B</i>. Currently, management of...
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MDPI AG
2020-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/15/5577 |
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| author | Gianluca De Rosa Immacolata Andolfo Roberta Marra Francesco Manna Barbara Eleni Rosato Achille Iolascon Roberta Russo |
| author_facet | Gianluca De Rosa Immacolata Andolfo Roberta Marra Francesco Manna Barbara Eleni Rosato Achille Iolascon Roberta Russo |
| author_sort | Gianluca De Rosa |
| collection | DOAJ |
| description | 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 <i>SEC23B</i>. 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 <i>SEC23B</i>-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 <i>SEC23B</i>-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. |
| first_indexed | 2024-03-10T17:58:59Z |
| format | Article |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T17:58:59Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-df481ac1554142bcad16bca364f911322023-11-20T09:02:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-08-012115557710.3390/ijms21155577RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 PathwayGianluca De Rosa0Immacolata Andolfo1Roberta Marra2Francesco Manna3Barbara Eleni Rosato4Achille Iolascon5Roberta Russo6Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, ItalyCeinge Biotecnologie Avanzate, 80145 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, ItalyCongenital 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 <i>SEC23B</i>. 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 <i>SEC23B</i>-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 <i>SEC23B</i>-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.https://www.mdpi.com/1422-0067/21/15/5577congenital dyserythropoietic anemia type IIactivin receptor II ligand trapin vitro drug treatment |
| spellingShingle | Gianluca De Rosa Immacolata Andolfo Roberta Marra Francesco Manna Barbara Eleni Rosato Achille Iolascon Roberta Russo 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 congenital dyserythropoietic anemia type II activin receptor II ligand trap in vitro drug treatment |
| title | RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway |
| title_full | RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway |
| title_fullStr | RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway |
| title_full_unstemmed | RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway |
| title_short | RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway |
| title_sort | rap 011 rescues the disease phenotype in a cellular model of congenital dyserythropoietic anemia type ii by inhibiting the smad2 3 pathway |
| topic | congenital dyserythropoietic anemia type II activin receptor II ligand trap in vitro drug treatment |
| url | https://www.mdpi.com/1422-0067/21/15/5577 |
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