Lineage skewing and genome instability underlie marrow failure in a zebrafish model of GATA2 deficiency

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. [Display omitted] •Zebrafish gata2a enhancer mutants recapitulate human GATA2 deficiency disease•A Gata2a/Cebpa axis maintains marrow cellularity and myeloid lineage output•Gata2a regulates expression of DNA damage repair and replication-associated genes•Progressive loss of npm1a in mutant HSPCs is associated with increased DNA damage Mahony et al. use single-cell genomics to uncover the molecular defects and examine progression to marrow failure in a zebrafish model of GATA2 deficiency. They show that Gata2a/Cebpa regulates marrow cellularity and myeloid lineage output, whereas HSPC survival and genome stability are protected by maintaining expression of DNA damage repair and replication-associated genes.