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

Tomasz Dobrzycki; Monika Krecsmarik; Cansu Koyunlar; Rossella Rispoli; Joke Peulen-Zink; Kirsten Gussinklo; Emma de Pater; Roger Patient; Rui Monteiro

doi:10.1101/516203

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

Tomasz Dobrzycki, Monika Krecsmarik, Cansu Koyunlar, Rossella Rispoli, Joke Peulen-Zink, Kirsten Gussinklo, Emma de Pater, Roger Patient, Rui Monteiro

Cancer and Genomic Sciences

Research output: Working paper/Preprint › Working paper

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 gata2a^Δi4/Δi4 larvae showdnormal numbers of HSPCs, a recovery mediated by Notch signalling driving gata2b expression in HE. However, gata2a^Δi4/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, gata2a^Δi4/Δi4 mutants developed acute myeloid leukemia. These mutants will be invaluable to explore the pathophysiology of MonoMAC syndrome in vivo.

Original language	English
Publisher	bioRxiv
Pages	1-38
Number of pages	38
DOIs	https://doi.org/10.1101/516203
Publication status	Published - 9 Jan 2019

Keywords

gata2a
gata2b
haemogenic endothelium
haematopoietic stem cells
haploinsufficiency
bone marrow failure
acute myeloid leukemia

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10.1101/516203Licence: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND)

Deletion of a conserved gata2a enhancer induces MonoMAC syndrome in zebrafish and reveals a requirement for gata2a in embryonic and adult haematopoiesis
Rui Monteiro (Speaker)
2019 → …
Activity: Academic and Industrial events › Conference, workshop or symposium

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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.",

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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

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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.

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KW - haploinsufficiency

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BT - 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

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Deletion of a conserved gata2a enhancer induces MonoMAC syndrome in zebrafish and reveals a requirement for gata2a in embryonic and adult haematopoiesis

Cite this