Abstract
Zebrafish has proven to be a versatile and reliable experimental in vivo tool to study human hematopoiesis and model hematological malignancies. Transgenic technologies enable the generation of specific leukemia types by the expression of human oncogenes under specific promoters. Using this technology, a variety of myeloid and lymphoid malignancies zebrafish models have been described. Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by the BCR-ABL1 fusion gene, derived from the t (9;22) translocation causing the Philadelphia Chromosome (Ph). The BCR-ABL1 protein is a constitutively activated tyrosine kinas inducing the leukemogenesis and resulting in an accumulation of immature leukemic cells into bone marrow and peripheral blood. To model Ph+ CML, a transgenic zebrafish line expressing the human BCR-ABL1 was generated by the Gal4/UAS system, and then crossed with the hsp70-Gal4 transgenic line. The new line named (BCR-ABL1pUAS:CFP/hsp70-Gal4), presented altered expression of hematopoietic markers during embryonic development compared to controls and transgenic larvae showed proliferating hematopoietic cells in the caudal hematopoietic tissue (CHT). The present transgenic zebrafish would be a robust CML model and a high-throughput drug screening tool.
Highlights
Thanks to anatomical and genetic similarities with human and other vertebrates, Zebrafish (Danio rerio) is an in vivo experimental model providing exceptional advantages in studying physiological or pathological processes and pathogenesis of different human diseases [1,2]
A deep in silico evaluation of zebrafish Abl1 protein with the human ABL1 counterpart indicated the presence of highly conserved tyrosine kinase domain and in particular the amino acids that are involved in bonds with tyrosine kinase inhibitors are preserved as reported in Supplementary Figure S2 (Figure S2)
While considering the remarkable results, the model proposed by the Authors required multiple activations of BCR-ABL1 expression by heat shock, it cannot be excluded that this method has forced the phenotype of the disease
Summary
Thanks to anatomical and genetic similarities with human and other vertebrates, Zebrafish (Danio rerio) is an in vivo experimental model providing exceptional advantages in studying physiological or pathological processes and pathogenesis of different human diseases [1,2]. Many downstream genes result deregulated, including those involved in JAK/STAT [20] and RAS signaling [21]; FOXO pathway [22,23]; cyclins and chaperone [24] These lead to genomic instability [25], abnormal cellular proliferation and cell survival [24], and to selection and amplification of more aggressive CML sub-clones [26], with an accumulation of immature hematopoietic stem cells into the bone marrow and the peripheral blood [27]. The presenting model is featured by an early development of CML-like disease in embryos and is proposed as a new tool for a real-time observation of leukemic cells pathogenesis and analysis of signaling pathways affected downstream the fusion gene
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