A small molecule screening strategy with validation on human leukemia stem cells uncovers the therapeutic efficacy of kinetin riboside
A small molecule screening strategy with validation on human leukemia stem cells uncovers the therapeutic efficacy of kinetin riboside
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DOI：
10.1182/blood-2011-01-330019
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发表时间：
2012-02-02
期刊：
影响因子：
20.3
通讯作者：
Dick, John E.
中科院分区：
文献类型：
--
作者：
McDermott, Sean P.;Eppert, Kolja;Dick, John E.
控制造血干细胞（hsc）和白血病起始细胞（l - ic）的基因调控网络是相互纠缠的。因此，发现靶向l - ic而不影响HSC的化合物是一项有吸引力但困难的努力。目前，大多数筛选方法无法对正常造血干细胞/祖细胞（HSPCs）的化合物进行反筛选。在这里，我们提出了一种多步骤的体外和体内方法来鉴定急性髓性白血病（AML）中可以靶向L-ICs的化合物。对来自人类实验性白血病发生模型的新型白血病细胞系进行了4000种化合物的高通量筛选，获得了80个命中，其中10个对HSPC的毒性较小。我们在AML l - ic和HSPCs上鉴定了一种单一化合物——动蛋白核苷（KR）。在63例原发性白血病中，KR显示出与标准治疗方法相当的疗效。在体外，KR靶向l - ic富集的CD34(+)CD38(-) AML部分，同时保留hspc富集的部分，尽管这些作用在体内对HSC的影响有所减轻。在体内检测时，KR消除了4个原发性AML样本中2个的L-IC，并强调了体内L-IC和HSC检测对测量功能的重要性。总的来说，我们提供了一种新的方法来筛选大型药物库，以发现抗l - ic化合物用于人类白血病。(血。2012;119 (5):1200 - 1207)
Gene regulatory networks that govern hematopoietic stem cells (HSCs) and leukemia-initiating cells (L-ICs) are deeply entangled. Thus, the discovery of compounds that target L-ICs while sparing HSC is an attractive but difficult endeavor. Presently, most screening approaches fail to counter-screen compounds against normal hematopoietic stem/progenitor cells (HSPCs). Here, we present a multistep in vitro and in vivo approach to identify compounds that can target L-ICs in acute myeloid leukemia (AML). A high-throughput screen of 4000 compounds on novel leukemia cell lines derived from human experimental leukemogenesis models yielded 80 hits, of which 10 were less toxic to HSPC. We characterized a single compound, kinetin riboside (KR), on AML L-ICs and HSPCs. KR demonstrated comparable efficacy to standard therapies against blast cells in 63 primary leukemias. In vitro, KR targeted the L-IC-enriched CD34(+)CD38(-) AML fraction, while sparing HSPC-enriched fractions, although these effects were mitigated on HSC assayed in vivo. KR eliminated L-ICs in 2 of 4 primary AML samples when assayed in vivo and highlights the importance of in vivo L-IC and HSC assays to measure function. Overall, we provide a novel approach to screen large drug libraries for the discovery of anti-L-IC compounds for human leukemias. (Blood. 2012;119(5):1200-1207)