The transcription factor Gata2 is required to produce and maintain haematopoietic stem and progenitor cells (HSPCs) in development and adult haematopoiesis. Mutations in GATA2 lead to GATA2 deficiency syndrome and predispose patients to acquire leukaemia. Here we use zebrafish gata2a enhancer deletion mutants and single cell transcriptomics to understand how GATA2 mediates survival and differentiation of haematopoietic stem cells in GATA2 deficiency. gata2a mutants show marrow failure from 6 months post-fertilization (mpf), accompanied by neutropenia and erythrocytosis. Single cell transcriptional profiling of the adult kidney marrow demonstrated that HSPCs express elevated expression of erythroid- and decreased expression of myeloid genes, including cebpa. This is associated with a lineage skewing towards the erythroid fate at the expense of the myeloid fate. Thus, Gata2a is required to initiate and maintain lineage priming in HSPCs, favouring myeloid differentiation. Gata2a regulates expression of multiple targets associated with replication and DNA damage repair, including npm1a, a zebrafish NPM1 orthologue. Accordingly, mutant marrow cells show increased DNA damage associated with progressive loss of npm1a expression with age. This effect was replicated by inhibiting NPM1 activity in murine HPC7 progenitor cells. We propose that the impaired DDR leads to marrow failure in GATA2 deficiency. This leads to increased genomic instability in the surviving HSPCs, favouring acquisition of secondary leukaemogenic mutations.
- Downloaded 148 times
- Download rankings, all-time:
- Site-wide: 158,126
- In cancer biology: 4,863
- Year to date:
- Site-wide: 67,309
- Since beginning of last month:
- Site-wide: 114,225
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!