Lineage skewing and genome instability underlie marrow failure in a zebrafish model of GATA2 deficiency
Christopher B. Mahony,
Lucy Copper,
Pavle Vrljicak,
Boris Noyvert,
Chrystala Constantinidou,
Sofia Browne,
Yi Pan,
Claire Palles,
Sascha Ott,
Martin R. Higgs,
Rui Monteiro
Affiliations
Christopher B. Mahony
Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Lucy Copper
Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Cancer Research UK Birmingham Centre, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Pavle Vrljicak
Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK
Boris Noyvert
Centre for Computational Biology, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Chrystala Constantinidou
Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK; Bioinformatics Research Technology Platform, University of Warwick, Coventry, UK
Sofia Browne
Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Yi Pan
Centre for Computational Biology, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Claire Palles
Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Sascha Ott
Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK; Bioinformatics Research Technology Platform, University of Warwick, Coventry, UK
Martin R. Higgs
Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Rui Monteiro
Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Corresponding author
Summary: Inherited bone marrow failure associated with heterozygous mutations in GATA2 predisposes toward hematological malignancies, but the mechanisms remain poorly understood. Here, we investigate the mechanistic basis of marrow failure in a zebrafish model of GATA2 deficiency. Single-cell transcriptomics and chromatin accessibility assays reveal that loss of gata2a leads to skewing toward the erythroid lineage at the expense of myeloid cells, associated with loss of cebpa expression and decreased PU.1 and CEBPA transcription factor accessibility in hematopoietic stem and progenitor cells (HSPCs). Furthermore, gata2a mutants show impaired expression of npm1a, the zebrafish NPM1 ortholog. Progressive loss of npm1a in HSPCs is associated with elevated levels of DNA damage in gata2a mutants. Thus, Gata2a maintains myeloid lineage priming through cebpa and protects against genome instability and marrow failure by maintaining expression of npm1a. Our results establish a potential mechanism underlying bone marrow failure in GATA2 deficiency.
