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Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay
The megakaryocyte/erythroid transient myeloproliferative disorder (TMD) in newborns with Down syndrome (DS) occurs when Nterminal truncating mutations of the hemopoietic transcription factor GATA1, that produce GATA1short protein (GATA1s), are acquired early in development. Prior work has shown that...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Fondazione Ferrata Storti
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018159/ https://www.ncbi.nlm.nih.gov/pubmed/32527952 http://dx.doi.org/10.3324/haematol.2019.244541 |
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author | Juban, Gaëtan Sakakini, Nathalie Chagraoui, Hedia Hernandez, David Cruz Cheng, Qian Soady, Kelly Stoilova, Bilyana Garnett, Catherine Waithe, Dominic Otto, Georg Doondeea, Jessica Usukhbayar, Batchimeg Karkoulia, Elena Alexiou, Maria Strouboulis, John Morrissey, Edward Roberts, Irene Porcher, Catherine Vyas, Paresh |
author_facet | Juban, Gaëtan Sakakini, Nathalie Chagraoui, Hedia Hernandez, David Cruz Cheng, Qian Soady, Kelly Stoilova, Bilyana Garnett, Catherine Waithe, Dominic Otto, Georg Doondeea, Jessica Usukhbayar, Batchimeg Karkoulia, Elena Alexiou, Maria Strouboulis, John Morrissey, Edward Roberts, Irene Porcher, Catherine Vyas, Paresh |
author_sort | Juban, Gaëtan |
collection | PubMed |
description | The megakaryocyte/erythroid transient myeloproliferative disorder (TMD) in newborns with Down syndrome (DS) occurs when Nterminal truncating mutations of the hemopoietic transcription factor GATA1, that produce GATA1short protein (GATA1s), are acquired early in development. Prior work has shown that murine GATA1s, by itself, causes a transient yolk sac myeloproliferative disorder. However, it is unclear where in the hemopoietic cellular hierarchy GATA1s exerts its effects to produce this myeloproliferative state. Here, through a detailed examination of hemopoiesis from murine GATA1s embryonic stem cells (ESC) and GATA1s embryos we define defects in erythroid and megakaryocytic differentiation that occur late in hemopoiesis. GATA1s causes an arrest late in erythroid differentiation in vivo, and even more profoundly in ESC-derived cultures, with a marked reduction of Ter-119 cells and reduced erythroid gene expression. In megakaryopoiesis, GATA1s causes a differentiation delay at a specific stage, with accumulation of immature, kit-expressing CD41hi megakaryocytic cells. In this specific megakaryocytic compartment, there are increased numbers of GATA1s cells in S-phase of the cell cycle and a reduced number of apoptotic cells compared to GATA1 cells in the same cell compartment. There is also a delay in maturation of these immature GATA1s megakaryocytic lineage cells compared to GATA1 cells at the same stage of differentiation. Finally, even when GATA1s megakaryocytic cells mature, they mature aberrantly with altered megakaryocyte-specific gene expression and activity of the mature megakaryocyte enzyme, acetylcholinesterase. These studies pinpoint the hemopoietic compartment where GATA1s megakaryocyte myeloproliferation occurs, defining where molecular studies should now be focused to understand the oncogenic action of GATA1s. |
format | Online Article Text |
id | pubmed-8018159 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Fondazione Ferrata Storti |
record_format | MEDLINE/PubMed |
spelling | pubmed-80181592021-04-05 Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay Juban, Gaëtan Sakakini, Nathalie Chagraoui, Hedia Hernandez, David Cruz Cheng, Qian Soady, Kelly Stoilova, Bilyana Garnett, Catherine Waithe, Dominic Otto, Georg Doondeea, Jessica Usukhbayar, Batchimeg Karkoulia, Elena Alexiou, Maria Strouboulis, John Morrissey, Edward Roberts, Irene Porcher, Catherine Vyas, Paresh Haematologica Article The megakaryocyte/erythroid transient myeloproliferative disorder (TMD) in newborns with Down syndrome (DS) occurs when Nterminal truncating mutations of the hemopoietic transcription factor GATA1, that produce GATA1short protein (GATA1s), are acquired early in development. Prior work has shown that murine GATA1s, by itself, causes a transient yolk sac myeloproliferative disorder. However, it is unclear where in the hemopoietic cellular hierarchy GATA1s exerts its effects to produce this myeloproliferative state. Here, through a detailed examination of hemopoiesis from murine GATA1s embryonic stem cells (ESC) and GATA1s embryos we define defects in erythroid and megakaryocytic differentiation that occur late in hemopoiesis. GATA1s causes an arrest late in erythroid differentiation in vivo, and even more profoundly in ESC-derived cultures, with a marked reduction of Ter-119 cells and reduced erythroid gene expression. In megakaryopoiesis, GATA1s causes a differentiation delay at a specific stage, with accumulation of immature, kit-expressing CD41hi megakaryocytic cells. In this specific megakaryocytic compartment, there are increased numbers of GATA1s cells in S-phase of the cell cycle and a reduced number of apoptotic cells compared to GATA1 cells in the same cell compartment. There is also a delay in maturation of these immature GATA1s megakaryocytic lineage cells compared to GATA1 cells at the same stage of differentiation. Finally, even when GATA1s megakaryocytic cells mature, they mature aberrantly with altered megakaryocyte-specific gene expression and activity of the mature megakaryocyte enzyme, acetylcholinesterase. These studies pinpoint the hemopoietic compartment where GATA1s megakaryocyte myeloproliferation occurs, defining where molecular studies should now be focused to understand the oncogenic action of GATA1s. Fondazione Ferrata Storti 2020-06-11 /pmc/articles/PMC8018159/ /pubmed/32527952 http://dx.doi.org/10.3324/haematol.2019.244541 Text en Copyright© 2021 Ferrata Storti Foundation http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
spellingShingle | Article Juban, Gaëtan Sakakini, Nathalie Chagraoui, Hedia Hernandez, David Cruz Cheng, Qian Soady, Kelly Stoilova, Bilyana Garnett, Catherine Waithe, Dominic Otto, Georg Doondeea, Jessica Usukhbayar, Batchimeg Karkoulia, Elena Alexiou, Maria Strouboulis, John Morrissey, Edward Roberts, Irene Porcher, Catherine Vyas, Paresh Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay |
title | Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay |
title_full | Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay |
title_fullStr | Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay |
title_full_unstemmed | Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay |
title_short | Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay |
title_sort | oncogenic gata1 causes stage-specific megakaryocyte differentiation delay |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018159/ https://www.ncbi.nlm.nih.gov/pubmed/32527952 http://dx.doi.org/10.3324/haematol.2019.244541 |
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