Journal article
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, v 21(15), pp 1-11
04 Aug 2020
PMID: 32759740
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 inSEC23B. 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 ofSEC23B-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 theseSEC23B-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.
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Details
- Title
- RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway
- Creators
- Gianluca De Rosa - University of Naples Federico IIImmacolata Andolfo - University of Naples Federico IIRoberta Marra - University of Naples Federico IIFrancesco Manna - Ceinge Biotecnologie AvanzateBarbara Eleni Rosato - University of Naples Federico IIAchille Iolascon - University of Naples Federico IIRoberta Russo - University of Naples Federico II
- Publication Details
- International journal of molecular sciences, v 21(15), pp 1-11
- Publisher
- Mdpi
- Number of pages
- 11
- Grant note
- 3978026 / European Hematology Association (EHA) Compagnia di San Paolo Programme STAR - UniNA CIVP18A1857-CoDysAn / Spanish foundation "Ramon Areces"
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000559233200001
- Scopus ID
- 2-s2.0-85089171121
- Other Identifier
- 991022004870404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Multidisciplinary