NOTCH1-induced T-cell leukemia in transgenic zebrafish
NOTCH1-induced T-cell leukemia in transgenic zebrafish
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DOI：
10.1038/sj.leu.2404546
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发表时间：
2007-03-01
期刊：
影响因子：
11.4
通讯作者：
Griffin, J. D.
中科院分区：
文献类型：
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作者：
Chen, J.;Jette, C.;Griffin, J. D.
在约60%的T细胞急性淋巴细胞白血病（T-ALL）患者中发现了NOTCH 1基因的激活突变。为了研究改变的Notch信号传导诱导白血病的分子机制，产生了人NOTCH 1诱导的T细胞白血病的斑马鱼模型。7 16马赛克鱼开发的T细胞淋巴增生性疾病在约5个月。这些肿瘤细胞广泛侵入整个鱼的组织，并在移植到受辐射的鱼时引起侵袭性和致命的白血病。然而，稳定的转基因鱼表现出较长的潜伏期白血病发作。当稳定的转基因品系与另一个过表达斑马鱼bcl 2基因的品系杂交时，白血病的发作显著加速，表明Notch途径和bcl 2介导的抗凋亡途径之间的协同作用。逆转录-聚合酶链反应分析显示Notch靶基因如her 6和her 9在NOTCH 1诱导的白血病中高度表达。该模型检测NOTCH 1和bcl 2之间强相互作用的能力表明，遗传修饰筛选很有可能揭示出其他可以与NOTCH 1合作诱导T-ALL的基因。
Activating mutations in the NOTCH1 gene have been found in about 60% of patients with T-cell acute lymphoblastic leukemia (T-ALL). In order to study the molecular mechanisms by which altered Notch signaling induces leukemia, a zebrafish model of human NOTCH1-induced T-cell leukemia was generated. Seven of sixteen mosaic fish developed a T-cell lymphoproliferative disease at about 5 months. These neoplastic cells extensively invaded tissues throughout the fish and caused an aggressive and lethal leukemia when transplanted into irradiated recipient fish. However, stable transgenic fish exhibited a longer latency for leukemia onset. When the stable transgenic line was crossed with another line overexpressing the zebrafish bcl2 gene, the leukemia onset was dramatically accelerated, indicating synergy between the Notch pathway and the bcl2-mediated antiapoptotic pathway. Reverse transcription-polymerase chain reaction analysis showed that Notch target genes such as her6 and her9 were highly expressed in NOTCH1-induced leukemias. The ability of this model to detect a strong interaction between NOTCH1 and bcl2 suggests that genetic modifier screens have a high likelihood of revealing other genes that can cooperate with NOTCH1 to induce T-ALL.