Peering through zebrafish to understand inherited bone marrow failure syndromes.

Inherited bone marrow failure syndromes are experiments of nature characterized by impaired hematopoiesis with cancer and leukemia predisposition. The mutations associated with inherited bone marrow failure syndromes affect fundamental cellular pathways, such as DNA repair, telomere maintenance, or proteostasis. How these disturbed pathways fail to produce sufficient blood cells and lead to leukemogenesis are not understood. The rarity of inherited cytopenias, the paucity of affected primary human hematopoietic cells, and the sometime inadequacy of murine or induced pluripotential stem cell models mean it is difficult to acquire a greater understanding of them. Zebrafish offer a model organism to study gene functions. As vertebrates, zebrafish share with humans many orthologous genes involved in blood disorders. As a model organism, zebrafish provide advantages that include rapid development of transparent embryos, high fecundity (providing large numbers of mutant and normal siblings), and a large collection of mutant and transgenic lines useful for investigating the blood system and other tissues during development. Importantly, recent advances in genomic editing in zebrafish can speedily validate the new genes or novel variants discovered in clinical investigation as causes for marrow failure. Here we review zebrafish as a model organism that phenocopies Fanconi anemia, Diamond-Blackfan anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia, and severe congenital neutropenia. Two important insights, provided by modeling inherited cytopenias in zebrafish, widen understanding of ribosome biogenesis and TP53 in mediating marrow failure and non-hematologic defects. They suggest that TP53-independent pathways contribute to marrow failure. In addition, zebrafish provide an attractive model organism for drug development.