Danio rerio: Small Fish Making a Big Splash in Leukemia

Abstract

Zebrafish (Danio rerio) are widely used for developmental biology studies. In the past decade, D. rerio have become an important oncology model as well. Leukemia is one type of cancer where zebrafish are particularly valuable. As vertebrates, fish have great anatomic and biologic similarity to humans, including their hematopoietic and immune systems. As an experimental platform, D. rerio offer many advantages that mammalian models lack. These include their ease of genetic manipulation, capacity for imaging, and suitability for large-scale phenotypic and drug screens. In this review, we present examples of these strategies and others to illustrate how zebrafish have been and can be used to study leukemia. Besides appraising the techniques researchers apply and introducing the leukemia models they have created, we also highlight recent and exciting discoveries made using D. rerio with an eye to where the field is likely headed.

Molecularly distinct models of zebrafish Myc-induced B cell leukemia

“…The first transgenic zebrafish leukemia model was created 15 years ago and targeted murine c- Myc ( mMyc ) to thymocytes of AB strain zebrafish, leading to the rapid development of T-cell acute lymphoblastic leukemia (T-ALL) [3]. Additional genetic models were subsequently developed that result in induction of T-ALL [4], but B-cell leukemia models lagged behind [5, 6].…”

Tackling Acute Lymphoblastic Leukemia—One Fish at a Time

“…Not only was this the first transgenic ALL model in D. rerio , but also the first zebrafish cancer model overall. Now, the number of zebrafish T-ALL models has reached double digits, as summarized below [12,13,14,15] (Table 1).…”

“…Few reports of zebrafish B-ALL exist, although differences between D. rerio and human B cells are comparably similar to those between T cells of these species [77]. The many successful zebrafish T-ALL models suggest D. rerio can likely emulate several human B-ALL subtypes, but currently, zebrafish B-ALL models lag behind [13,15]. Here, we will review the three zebrafish B-ALL models reported to date (Table 1), but it is likely many others will soon follow.…”

“…Howe et al showed that ~70% of human genes have zebrafish orthologues [11]; this aids in correlating gene expression in zebrafish cancers to their human counterparts and with designing transgenic zebrafish that express human (or other mammalian) genes. D. rerio have repeatedly proven to be an excellent model to study blood disorders and hematologic cancers [12,13,14,15,16,17,18,19]. The zebrafish adaptive immune system resembles that of humans [20], and zebrafish thymic architecture is also similar to mammals, containing distinct cortical and medullary regions that compartmentalize maturing T cells [21].…”

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“…However, despite the fact that zebrafish T-ALL models had proven to be fertile grounds for study, B-ALL modeling in D. rerio had not been fruitful, with only one low penetrance and long latency line reported [54]. This was curious because a zebrafish recombination activating gene 2 (rag2) promoter-active in both immature T and B cells-was used to regulate most of these transgenic oncoproteins in the various T-ALL lines, yet D. rerio B-ALL had not been reported in them [55,56]. Overall, since B-ALL is the more prevalent type in patients, the lack of B-lineage models was particularly unfortunate.…”