| Autor: |
El Hoss S; Red Cell Haematology Lab, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King's College London. sara.el-hoss@institutimagine.org., Shangaris P; Women and Children's Health, School of Life Course and Population Sciences, King's College London, London, United Kingdom; Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom; Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London., Brewin J; Red Cell Haematology Lab, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King's College London, United Kingdom; Department of Haematological Medicine, King's College Hospital, London., Psychogyiou ME; Red Cell Haematology Lab, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King's College London., Ng C; Red Cell Haematology Lab, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King's College London., Pedler L; Red Cell Haematology Lab, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King's College London., Rooks H; Red Cell Haematology Lab, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King's College London., Gotardo ÉMF; Hematology and Transfusion Center, Universidade Estadual de Campinas (UNICAMP), Campinas - São Paulo., Gushiken LFS; Hematology and Transfusion Center, Universidade Estadual de Campinas (UNICAMP), Campinas - São Paulo., Brito PL; Hematology and Transfusion Center, Universidade Estadual de Campinas (UNICAMP), Campinas - São Paulo., Nicolaides KH; Women and Children's Health, School of Life Course and Population Sciences, King's College London, London, United Kingdom; Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London., Conran N; Hematology and Transfusion Center, Universidade Estadual de Campinas (UNICAMP), Campinas - São Paulo., Rees DC; Red Cell Haematology Lab, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King's College London, United Kingdom; Department of Haematological Medicine, King's College Hospital, London., Strouboulis J; Red Cell Haematology Lab, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King's College London. john.strouboulis@kcl.ac.uk. |
| Abstrakt: |
Ineffective erythropoiesis (IE) is defined as the abnormal differentiation and excessive destruction of erythroblasts in the marrow, accompanied by an expanded progenitor compartment and relative reduction in the production of reticulocytes. It is a defining feature of many types of anemia, including beta-thalassemia. GATA1 is an essential transcription factor for erythroid differentiation, known to be implicated in hematological conditions presenting with IE, including beta-thalassemia and congenital dyserythropoietic anemia. However, little is known about the role of GATA1 in the erythropoietic defects recently described in sickle cell anemia (SCA). In the present study, we performed a detailed characterization of the role of GATA1 and ineffective erythropoiesis in SCA using both invitro and in-vivo assay systems. We demonstrate a significant decrease in GATA1 protein levels during SCA erythropoiesis and a concomitant increase in oxidative stress. Furthermore, we found that an increase in the activity of the inflammatory caspase, caspase 1, was driving the decrease in GATA1 levels during SCA erythropoiesis and that, upon inhibition of caspase 1 activity, SCA erythropoiesis was rescued and GATA1 levels partially restored. Our study further elucidates the defect in erythropoiesis in SCA, and may therefore help in the development of novel approaches to normalise the bone marrow niche prior to stem cell transplantation, or facilitate the production of healthy stem cells for gene therapy. |
