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Zebrafish models of acute leukemias: Current models and future directions

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Abstract Acute myeloid leukemias (AML) and acute lymphoid leukemias (ALL) are heterogenous diseases encompassing a wide array of genetic mutations with both loss and gain of function phenotypes. Ultimately, these both result in the clonal overgrowth of blast cells in the bone marrow, peripheral blood, and other tissues. As a consequence of this, normal hematopoietic stem cell function is severely hampered. Technologies allowing for the early detection of genetic alterations and understanding of these varied molecular pathologies have helped to advance our treatment regimens toward personalized targeted therapies. In spite of this, both AML and ALL continue to be a major cause of morbidity and mortality worldwide, in part because molecular therapies for the plethora of genetic abnormalities have not been developed. This underscores the current need for better model systems for therapy development. This article reviews the current zebrafish models of AML and ALL and discusses how novel gene editing tools can be implemented to generate better models of acute leukemias. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease Technologies > Perturbing Genes and Generating Modified Animals
Hematopoiesis is the life‐long formation and turn‐over of blood cells. Hematopoietic stem cells (HSCs) is a multipotent clonal population that has the ability to self‐renew and differentiate into myeloid and lymphoid progenitors, which give rise to all functional cells of the blood. Different types of blood cancer originate from different types of blood cells. “Myeloid or myelogenous” leukemia originates from myeloid progenitors and “lymphoid or lymphoblastic” leukemia arises from lymphoid progenitors. Comparably, lymphoma and myeloma originate from lymphocytes and plasma cells, respectively
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CRISPR‐Cas9 components to inject in zebrafish embryos for the generation of zebrafish knock‐in models. (i). mRNA for expression of Cas9 endonuclease. (ii). Genomic single‐guide RNA for cleavage of target site of genomic locus. (iii). Donor linear DNA with large homology arms for conventional CRISPR/Cas9 protocol. (iv). Universal single‐guide RNA for cleavage of donor vector and release of short homology arms (GeneWeld protocol). (v). Donor vector carrying cargo DNA to be inserted at target site and homology arms, flanked by Universal gRNA Site (URS)
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Xenograft between human and zebrafish. Human tumor cells are harvested and cultured in a dish in preparation for a xenograft in zebrafish. The xenograft can take place in the juvenile or adult stage of zebrafish and the fluorescent cells are easily visualized in vivo during the transluscent stage of zebrafish development
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Timeline of anatomical locations of hematopoiesis in zebrafish and humans. Primitive blood cells emerge in the intermediate cells mass in zebrafish, the equivalent to the human yolk sac. Subsequently, definitive blood cells (HSCs) first emerge in the aorta‐gonad‐mesonephros (AGM) in humans and in the aorta (AGM‐like) in zebrafish. HSCs now enter circulation and proliferate in the caudal hematopoietic tissue (CHT) in fish and fetal liver in humans. Hereafter, HSCs colonize the kidney marrow (fish) or bone marrow (humans), which is where hematopoiesis will occur during the organism's lifetime. dpf, days postfertilization; hpf, hours postfertilization
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Benefits of zebrafish models in cancer research. This figure depicts the benefits of zebrafish in research in general as well as specifically in leukemia research. Zebrafish are affordable and easy to maintain in laboratories. Every week, sexually mature zebrafish lay and fertilize eggs that are easily accessible for genetic manipulation at the single cell stage, drug screens, and in vivo fluorescent cell visualization throughout development. Zebrafish are good models for xenograft manipulation at several stages as well. Many human and zebrafish genes are genetically similar and the hematopoeitc pathway is conserved
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Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease