Zebrafish screen identifies novel compound with selective toxicity against leukemia
Zebrafish screen identifies novel compound with selective toxicity against leukemia
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DOI：
10.1182/blood-2011-12-398818
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发表时间：
2012-06-14
期刊：
影响因子：
20.3
通讯作者：
Trede, Nikolaus S.
中科院分区：
文献类型：
--
作者：
Ridges, Suzanne;Heaton, Will L.;Trede, Nikolaus S.
为了检测靶向抗白血病药物，我们设计了一种新颖的、高含量的体内筛选方法，使用基因工程的、报告t细胞的斑马鱼。我们利用正常T淋巴细胞和恶性T淋巴细胞之间的发育相似性，在斑马鱼幼虫中筛选一个小分子文库，通过简单的视觉读取来对抗未成熟T细胞。在筛选了26400个分子后，我们确定了Lenaldekar (LDK)，这是一种消除发育中的斑马鱼中未成熟T细胞而不影响其他细胞类型细胞周期的化合物。LDK在脊椎动物中具有良好的耐受性，并在患有cmyc诱导的t细胞急性淋巴细胞白血病（T-ALL）的成年斑马鱼中诱导长期缓解。LDK导致PI3激酶/AKT/mTOR通路成员的去磷酸化，并延迟敏感细胞的有丝分裂晚期。在人类癌症中，LDK选择性地影响造血恶性肿瘤系和原发性白血病的生存，包括治疗难治性B-ALL和慢性骨髓性白血病样本，并抑制人类T-ALL异种移植物的生长。这项工作证明了我们使用斑马鱼进行抗肿瘤候选药物鉴定的方法的实用性，并为靶向白血病治疗提供了一种新的方法。虽然我们的研究主要集中在白血病治疗上，但这种筛查方法具有广泛的意义，因为它可以转化为涉及发育受阻细胞恶性变性的其他癌症类型。[血液杂志];2012;119(24):5621-5631]
To detect targeted antileukemia agents we have designed a novel, high-content in vivo screen using genetically engineered, T-cell reporting zebrafish. We exploited the developmental similarities between normal and malignant T lymphoblasts to screen a small molecule library for activity against immature T cells with a simple visual readout in zebrafish larvae. After screening 26 400 molecules, we identified Lenaldekar (LDK), a compound that eliminates immature T cells in developing zebrafish without affecting the cell cycle in other cell types. LDK is well tolerated in vertebrates and induces long-term remission in adult zebrafish with cMYC-induced T-cell acute lymphoblastic leukemia (T-ALL). LDK causes dephosphorylation of members of the PI3 kinase/AKT/mTOR pathway and delays sensitive cells in late mitosis. Among human cancers, LDK selectively affects survival of hematopoietic malignancy lines and primary leukemias, including therapy-refractory B-ALL and chronic myelogenous leukemia samples, and inhibits growth of human T-ALL xenografts. This work demonstrates the utility of our method using zebrafish for antineoplastic candidate drug identification and suggests a new approach for targeted leukemia therapy. Although our efforts focused on leukemia therapy, this screening approach has broad implications as it can be translated to other cancer types involving malignant degeneration of developmentally arrested cells. (Blood. 2012; 119(24):5621-5631)