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Ferrata Storti Foundation
Haematologica 2021 Volume 106(4):1106-1119
Hematopoiesis
Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay
Gaëtan Juban,1a* Nathalie Sakakini,1,2b* Hedia Chagraoui,1
David Cruz Hernandez,1,2 Qian Cheng,3 Kelly Soady,1,2 Bilyana Stoilova,1,2
Catherine Garnett,1,2 Dominic Waithe,3 Georg Otto,1c Jessica Doondeea,1,2
Batchimeg Usukhbayar,1,2 Elena Karkoulia,4 Maria Alexiou,5d
John Strouboulis,4e Edward Morrissey,5 Irene Roberts,1,2,6
Catherine Porcher1# and Paresh Vyas1,2,7#
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MRC Molecular Hematology Unit WIMM, University of Oxford, Oxford, UK; Haematology
Theme Oxford Biomedical Research Center, Oxford, UK; 3Center for Computational Biology WIMM, University of Oxford, Oxford, UK; 4Institute of Molecular Biology and Biotechnology, Foundation of Research & Technology-Hellas, Heraklion, Crete Greece; 5Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece; 6Department of Pediatrics University of Oxford, Oxford, UK and 7Department of Hematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
*GJ and NS contributed equally as co-first authors. #CP and PV contributed euqally as co-senior authors.
aCurrent address: Institut NeuroMyoGène, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U1217, Université Lyon, Lyon, France.
bCurrent address: Cambridge Stem Cell Institute, Cambridge, UK.
cCurrent address: Genetics and Genomic Medicine, University College London Institute of Child Health, London, UK.
dCurrent address: Department of Dentistry, University of Alberta, Edmonton, Alberta, Canada.
eCurrent address: Rayne Institute School of Cancer & Pharmaceutical Sciences, King’s College London, London, UK
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 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 accumu- lation 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 apop- totic 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 differentia- tion. 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.
Correspondence:
PARESH VYAS
paresh.vyas@imm.ox.ac.uk
GAËTAN JUBAN
gaetan.juban@univ-lyon1.fr
Received: December 8, 2019. Accepted: May 20, 2020. Pre-published: June 11, 2020
https://doi.org/10.3324/haematol.2019.244541
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