Heritable T-cell malignancy models established in a zebrafish phenotypic screen
Heritable T-cell malignancy models established in a zebrafish phenotypic screen
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DOI：
10.1038/leu.2009.116
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发表时间：
2009-10-01
期刊：
影响因子：
11.4
通讯作者：
Trede, N. S.
中科院分区：
文献类型：
--
作者：
Frazer, J. K.;Meeker, N. D.;Trede, N. S.
T 细胞肿瘤在儿科肿瘤学中很常见，包括急性淋巴细胞白血病 (T-ALL) 和淋巴母细胞淋巴瘤 (T-LBL)。这些癌症的预后比 B 细胞癌症更差，而且它们的治疗具有显着的发病率。尽管许多儿科恶性肿瘤具有特征性易位，但大多数 T 淋巴细胞衍生疾病缺乏细胞遗传学标志。由于缺乏这些信息丰富的病变，对其分子发病机制的了解并不完整。尽管大部分病例中都会出现 NOTCH1 通路的失调，但 T 细胞恶性肿瘤的许多其他遗传病变尚未确定。为了解决这一缺陷，我们率先在斑马鱼（Danio rerio）中进行了表型驱动的正向遗传筛选。我们利用 T 淋巴细胞特异性表达增强型绿色荧光蛋白 (EGFP) 的转基因鱼，进行了化学诱变，筛选了动物的 GFP(+) 肿瘤，并鉴定了多个具有 T 细胞恶性肿瘤遗传倾向的品系。在每个细胞系中，浸润模式和形态学外观均类似于人类 T-ALL 和 T-LBL。 T 细胞受体分析证实了它们的克隆性。恶性肿瘤是可移植的，并且含有白血病起始细胞，就像它们的人类相关细胞一样。总之，我们已经鉴定出多种斑马鱼突变体，它们再现了人类 T 细胞瘤形成并显示出可遗传的传播。这些脊椎动物模型为研究这些重要的人类癌症提供了新的遗传平台。白血病 (2009) 23, 1825-1835; doi：10.1038/leu.2009.116； 2009 年 6 月 11 日在线发布
T-cell neoplasias are common in pediatric oncology, and include acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LBL). These cancers have worse prognoses than their B-cell counterparts, and their treatments carry significant morbidity. Although many pediatric malignancies have characteristic translocations, most T-lymphocyte-derived diseases lack cytogenetic hallmarks. Lacking these informative lesions, insight into their molecular pathogenesis is less complete. Although dysregulation of the NOTCH1 pathway occurs in a substantial fraction of cases, many other genetic lesions of T-cell malignancy have not yet been determined. To address this deficiency, we pioneered a phenotype-driven forward-genetic screen in zebrafish (Danio rerio). Using transgenic fish with T-lymphocyte-specific expression of enhanced green fluorescent protein (EGFP), we performed chemical mutagenesis, screened animals for GFP(+) tumors, and identified multiple lines with a heritable predisposition to T-cell malignancy. In each line, the patterns of infiltration and morphological appearance resembled human T-ALL and T-LBL. T-cell receptor analyses confirmed their clonality. Malignancies were transplantable and contained leukemia-initiating cells, like their human correlates. In summary, we have identified multiple zebrafish mutants that recapitulate human T-cell neoplasia and show heritable transmission. These vertebrate models provide new genetic platforms for the study of these important human cancers. Leukemia (2009) 23, 1825-1835; doi: 10.1038/leu.2009.116; published online 11 June 2009