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Peering through zebrafish to understand inherited bone marrow failure syndromes
1Department of Pediatrics, Children’s Hospital of Richmond and Massey Cancer Center at Virginia Commonwealth University, Richmond, VA, USA; 2Department of Pediatrics, Stanley Manne Children's Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 3Department of Biochemistry and Molecular Biology, Medical University of Lublin, Poland; 4Department of Microbiology/Immunology, Virginia Commonwealth University, USA and 5Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, USA
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 path- ways fail to produce sufficient blood cells and lead to leukemogenesis are not understood. The rarity of inherited cytopenias, the paucity of affect- ed 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 organ- ism 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 trans- genic lines useful for investigating the blood system and other tissues dur- ing development. Importantly, recent advances in genomic editing in zebrafish can speedily validate the new genes or novel variants discov- ered 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 ribo- some biogenesis and TP53 in mediating marrow failure and non-hema- tologic defects. They suggest that TP53-independent pathways con- tribute to marrow failure. In addition, zebrafish provide an attractive model organism for drug development.
Introduction
The inherited bone marrow failure syndromes (IBMFs) comprise a diverse group of rare monogenic disorders that are phenotypically heterogeneous. They may involve a single or multiple lineage(s). The classic disorders are: Fanconi anemia (FA), Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome (SDS), dyskeratosis congenita (DC), severe congenital neutropenia (SCN), and congenital amegakaryocytic thrombocytopenia (CAMT). Besides their phenotypic character- izations, these syndromes correlate strongly with mutations involving a specific pathway. FA results from mutations in genes encoding components of the DNA damage response,1 DC in telomere maintenance,2 and DBA in ribosome function.3
Ferrata Storti Foundation
Haematologica 2019 Volume 104(1):13-24
Usua Oyarbide,1* Jacek Topczewski2,3 and Seth J. Corey1,4,5*
*Current address: Departments of Pediatrics, Translational Hematology and Oncology Research, and Cancer Biology, Cleveland Clinic, Cleveland, OH, USA
Correspondence:
coreys2@ccf.org
Received: August 20, 2018. Accepted: November 14, 2018. Pre-published: December 20, 2018.
doi:10.3324/haematol.2018.196105
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/1/13
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