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 hema-tological 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 asso-ciated with elevated levels of DNA damage in gata2a mutants. Thus, Gata2a maintains myeloid lineage prim-ing 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.

Automated summary

Through studying a zebrafish model of GATA2 deficiency, it was found that loss of the gata2a gene led to an overproduction of erythroid cells and a decrease in myeloid cells. This was associated with a decrease in cebpa expression and decreased accessibility of PU.1 and CEBPA transcription factors in hematopoietic stem and progenitor cells (HSPCs). In addition, the gata2a mutants showed impaired expression of npm1a, which was associated with elevated levels of DNA damage. Overall, Gata2a maintains myeloid lineage priming and protects against genome instability and bone marrow failure.