UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Oncogenic Gata1 Causes Stage-Specific Megakaryocyte Differentiation Delay

Juban, G; Sakakini, N; Chagraoui, H; Cruz Hernandez, D; Cheng, Q; Soady, K; Stoilova, B; ... Vyas, P; + view all (2020) Oncogenic Gata1 Causes Stage-Specific Megakaryocyte Differentiation Delay. Haematologica 10.3324/haematol.2019.244541. (In press). Green open access

[thumbnail of haematol.2019.244541.full.pdf]
Preview
Text
haematol.2019.244541.full.pdf - Accepted Version

Download (1MB) | Preview

Abstract

The megakaryocyte/erythroid Transient Myeloproliferative Disorder (TMD) in newborns with Down Syndrome (DS) occurs when N-terminal 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 ES cells and GATA1s embryos we define defects in erythroid and megakaryocytic differentiation that occur relatively late in hemopoiesis. GATA1s causes an arrest late in erythroid differentiation in vivo, and even more profoundly in ES-cell 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 cell cycle and 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 focussed to understand the oncogenic action of GATA1s.

Type: Article
Title: Oncogenic Gata1 Causes Stage-Specific Megakaryocyte Differentiation Delay
Location: Italy
Open access status: An open access version is available from UCL Discovery
DOI: 10.3324/haematol.2019.244541
Publisher version: https://doi.org/10.3324/haematol.2019.244541
Language: English
Additional information: This is an Open Access article published under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/).
Keywords: GATA1s, Hematopoiesis, Megakaryopoiesis, Red Cells, Transient Myeloproliferative Disorder
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10101912
Downloads since deposit
Loading...
64Downloads
Download activity - last month
Loading...
Download activity - last 12 months
Loading...
Downloads by country - last 12 months
1.Indonesia
1
2.United States
1

Archive Staff Only

View Item View Item