BCR-ABL1 转基因斑马鱼模型的开发重现慢性髓性白血病（CML）样疾病，并为 CML 机制提供新的见解。

Development of BCR-ABL1 Transgenic Zebrafish Model Reproducing Chronic Myeloid Leukemia (CML) Like-Disease and Providing a New Insight into CML Mechanisms.

机构信息

Unit of Biotechnology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.

Unit of Hematology, Department of Clinical and Experimental Sciences, University of Brescia, Bone Marrow Transplant Unit, ASST Spedali Civili, 25123 Brescia, Italy.

出版信息

Cells. 2021 Feb 19;10(2):445. doi: 10.3390/cells10020445.

DOI:10.3390/cells10020445

PMID:33669758

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7922348/

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 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 was generated by the Gal4/UAS system, and then crossed with the hsp70-Gal4 transgenic line. The new line named (pUAS: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.

摘要

斑马鱼已被证明是一种多功能且可靠的体内实验工具，可用于研究人类造血以及模拟血液系统恶性肿瘤。转基因技术可通过在特定启动子下表达人类癌基因来产生特定类型的白血病。利用这项技术，已经描述了多种骨髓性和淋巴性恶性肿瘤的斑马鱼模型。慢性髓细胞白血病（CML）是一种克隆性髓系增殖性肿瘤，其特征在于融合基因，源自导致费城染色体（Ph）的 t（9；22）易位。BCR-ABL1 蛋白是一种组成性激活的酪氨酸激酶，可诱导白血病发生，并导致不成熟的白血病细胞在骨髓和外周血中积聚。为了模拟 Ph+CML，通过 Gal4/UAS 系统生成了表达人的转基因斑马鱼系，然后与 hsp70-Gal4 转基因系杂交。新的系命名为（pUAS:CFP/hsp70-Gal4），与对照和转基因幼虫相比，在胚胎发育过程中造血标记物的表达发生改变，并且转基因幼虫的尾造血组织（CHT）中存在增殖性造血细胞。这种新型的转基因斑马鱼将成为一种强大的 CML 模型和高通量药物筛选工具。