Peering through zebrafish to understand inherited bone marrow failure syndromes

Abstract

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.

Loss of Sbds in zebrafish leads to neutropenia and pancreas and liver atrophy

“…Zebrafish polr1c mutants showed an upregulated Tp53 pathway (31). However, morpholinos may themselves trigger Tp53 activation (32), and other ribosomopathies suggest that Tp53-independent pathways also contribute to bone marrow failure (33). Very little is known about how SBDS affects development and tissue maintenance of the gastrointestinal system.…”

Zebrafish Models of Diamond-Blackfan Anemia: A Tool for Understanding the Disease Pathogenesis and Drug Discovery

“…These phenotypes were rescued by injection of wild-type rps19 mRNAs but not by mRNAs with patient-type mutations [14]. Subsequently, other RP gene knockdown models were also generated, and together with the rps19-knockdown embryos, these models have been used for exploring DBA pathogenesis [10].…”

“…Knockout mice harboring a homozygous mutation of the causative RP genes died in a very early stage of development, and the heterozygous mutants displayed no abnormal symptoms [7]. The zebrafish (Danio rerio) is a small freshwater fish originating from India and is a useful model animal for studying human diseases [9][10][11]. There are many attractive advantages of using zebrafish as a DBA model, including not only the fast development and transparency of embryos but also the conserved hematopoietic regulation in humans.…”

“…For these reasons, zebrafish have been recognized as a promising animal model of DBA, and several groups, including us, successfully developed valuable zebrafish models of this disease [10,14]. These models enabled us to gain an in-depth understanding of the disease mechanism and to provide platforms for empowering future studies.…”

Application of the Moran Model in Estimating Selection Coefficient of Mutated CSF3R Clones in the Evolution of Severe Congenital Neutropenia to Myeloid Neoplasia

“…Each of these clinically defined disorders are monogenic with mutations in one or more genes in a pathway. For example, Fanconi anemia results from germline mutations in genes involved in DNA repair and Diamond-Blackfan anemia in ribosome structure (Oyarbide et al, 2019). What is less well-understood are the somatic mutations that arise during transformation of a BMF syndrome to myeloid neoplasia (Rafei and DiNardo, 2019).…”