Division of Hematology/Oncology, Northwestern University, Chicago, IL 60611, USA.
Cell. 2012 Aug 3;150(3):575-89. doi: 10.1016/j.cell.2012.06.032.
The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.
细胞决定跳过有丝分裂成为多倍体的机制在很大程度上尚未确定。在这里，我们使用基于高内涵图像的筛选方法来鉴定可诱导巨核细胞白血病细胞多倍体化的小分子探针，并将其作为扰动剂来帮助理解这一过程。我们的研究表明，有五个调节多倍体化开关的激酶网络。此外，我们发现二甲基法舒地尔（diMF，H-1152P）选择性地增加了多倍体化、成熟细胞表面标志物的表达和恶性巨核细胞的凋亡。采用蛋白质组学和 shRNA 筛选的综合靶标鉴定方法表明，diMF 的一个主要靶标是 Aurora 激酶 A（AURKA）。我们进一步发现，AURKA 的选择性抑制剂 MLN8237（alisertib）可诱导急性巨核细胞白血病（AMKL）母细胞中的多倍体化和成熟巨核细胞标志物的表达，并在体内显示出强大的抗 AMKL 活性。我们的研究结果为支持 MLN8237 和 AMKL 中其他诱导多倍体化和分化的诱导剂的临床试验提供了依据。
