A zebrafish model for MonoMAC syndrome identifies an earlier role for gata2 in haemogenic endothelium programming and generation of haematopoietic stem cells

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A zebrafish model for MonoMAC syndrome identifies an earlier role for gata2 in haemogenic endothelium programming and generation of haematopoietic stem cells. / Dobrzycki, Tomasz; Krecsmarik, Monika; Koyunlar, Cansu; Rispoli, Rossella; Peulen-Zink, Joke; Gussinklo, Kirsten; Pater, Emma de; Patient, Roger; Monteiro, Rui.

bioRxiv, 2019. p. 1-38.

Research output: Working paper

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Dobrzycki, T., Krecsmarik, M., Koyunlar, C., Rispoli, R., Peulen-Zink, J., Gussinklo, K., Pater, E. D., Patient, R., & Monteiro, R. (2019). A zebrafish model for MonoMAC syndrome identifies an earlier role for gata2 in haemogenic endothelium programming and generation of haematopoietic stem cells. (pp. 1-38). bioRxiv. https://doi.org/10.1101/516203

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Author

Dobrzycki, Tomasz ; Krecsmarik, Monika ; Koyunlar, Cansu ; Rispoli, Rossella ; Peulen-Zink, Joke ; Gussinklo, Kirsten ; Pater, Emma de ; Patient, Roger ; Monteiro, Rui. / A zebrafish model for MonoMAC syndrome identifies an earlier role for gata2 in haemogenic endothelium programming and generation of haematopoietic stem cells. bioRxiv, 2019. pp. 1-38

Bibtex

@techreport{41c269357bf0462dae5442657949acce,
title = "A zebrafish model for MonoMAC syndrome identifies an earlier role for gata2 in haemogenic endothelium programming and generation of haematopoietic stem cells",
abstract = "Haematopoietic stem and progenitor cells (HSPCs) maintain the vertebrate blood system throughout life and their emergence from haemogenic endothelium (HE) is tightly regulated by transcription factors such as Gata2. Zebrafish have two orthologues of Gata2, Gata2a and Gata2b, the latter required for HSPC emergence. Here we deleted a conserved enhancer driving gata2a expression in endothelium (i4 enhancer) and showed that Gata2a is required for HE programming by regulating expression of gata2b and runx1. By 5 days, homozygous gata2aΔi4/Δi4 larvae showdnormal numbers of HSPCs, a recovery mediated by Notch signalling driving gata2b expression in HE. However, gata2aΔi4/Δi4 adults showed lymphoedema, susceptibility to infections and marrow hypocellularity, consistent with bone marrow failure of MonoMAC syndrome patients. Thus, Gata2a is required for HE programming and haematopoiesis in the adult. Like MonoMAC syndrome patients, gata2aΔi4/Δi4 mutants developed acute myeloid leukemia. These mutants will be invaluable to explore the pathophysiology of MonoMAC syndrome in vivo.",
keywords = "gata2a, gata2b, haemogenic endothelium, haematopoietic stem cells, haploinsufficiency, bone marrow failure, acute myeloid leukemia",
author = "Tomasz Dobrzycki and Monika Krecsmarik and Cansu Koyunlar and Rossella Rispoli and Joke Peulen-Zink and Kirsten Gussinklo and Pater, {Emma de} and Roger Patient and Rui Monteiro",
year = "2019",
month = jan
day = "9",
doi = "10.1101/516203",
language = "English",
pages = "1--38",
publisher = "bioRxiv",
type = "WorkingPaper",
institution = "bioRxiv",

}

RIS

TY - UNPB

T1 - A zebrafish model for MonoMAC syndrome identifies an earlier role for gata2 in haemogenic endothelium programming and generation of haematopoietic stem cells

AU - Dobrzycki, Tomasz

AU - Krecsmarik, Monika

AU - Koyunlar, Cansu

AU - Rispoli, Rossella

AU - Peulen-Zink, Joke

AU - Gussinklo, Kirsten

AU - Pater, Emma de

AU - Patient, Roger

AU - Monteiro, Rui

PY - 2019/1/9

Y1 - 2019/1/9

N2 - Haematopoietic stem and progenitor cells (HSPCs) maintain the vertebrate blood system throughout life and their emergence from haemogenic endothelium (HE) is tightly regulated by transcription factors such as Gata2. Zebrafish have two orthologues of Gata2, Gata2a and Gata2b, the latter required for HSPC emergence. Here we deleted a conserved enhancer driving gata2a expression in endothelium (i4 enhancer) and showed that Gata2a is required for HE programming by regulating expression of gata2b and runx1. By 5 days, homozygous gata2aΔi4/Δi4 larvae showdnormal numbers of HSPCs, a recovery mediated by Notch signalling driving gata2b expression in HE. However, gata2aΔi4/Δi4 adults showed lymphoedema, susceptibility to infections and marrow hypocellularity, consistent with bone marrow failure of MonoMAC syndrome patients. Thus, Gata2a is required for HE programming and haematopoiesis in the adult. Like MonoMAC syndrome patients, gata2aΔi4/Δi4 mutants developed acute myeloid leukemia. These mutants will be invaluable to explore the pathophysiology of MonoMAC syndrome in vivo.

AB - Haematopoietic stem and progenitor cells (HSPCs) maintain the vertebrate blood system throughout life and their emergence from haemogenic endothelium (HE) is tightly regulated by transcription factors such as Gata2. Zebrafish have two orthologues of Gata2, Gata2a and Gata2b, the latter required for HSPC emergence. Here we deleted a conserved enhancer driving gata2a expression in endothelium (i4 enhancer) and showed that Gata2a is required for HE programming by regulating expression of gata2b and runx1. By 5 days, homozygous gata2aΔi4/Δi4 larvae showdnormal numbers of HSPCs, a recovery mediated by Notch signalling driving gata2b expression in HE. However, gata2aΔi4/Δi4 adults showed lymphoedema, susceptibility to infections and marrow hypocellularity, consistent with bone marrow failure of MonoMAC syndrome patients. Thus, Gata2a is required for HE programming and haematopoiesis in the adult. Like MonoMAC syndrome patients, gata2aΔi4/Δi4 mutants developed acute myeloid leukemia. These mutants will be invaluable to explore the pathophysiology of MonoMAC syndrome in vivo.

KW - gata2a

KW - gata2b

KW - haemogenic endothelium

KW - haematopoietic stem cells

KW - haploinsufficiency

KW - bone marrow failure

KW - acute myeloid leukemia

UR - https://doi.org/10.1101/516203

U2 - 10.1101/516203

DO - 10.1101/516203

M3 - Working paper

SP - 1

EP - 38

BT - A zebrafish model for MonoMAC syndrome identifies an earlier role for gata2 in haemogenic endothelium programming and generation of haematopoietic stem cells

PB - bioRxiv

ER -