کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2035701 | 1072212 | 2012 | 15 صفحه PDF | دانلود رایگان |
SummaryThe 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.
Graphical AbstractFigure optionsDownload high-quality image (115 K)Download as PowerPoint slideHighlights
► Screen identifies > 200 compounds regulating megakaryocyte polyploidization
► Integrated target identification approach suggests regulatory kinase networks
► Aurora kinase A activity mediates megakaryocyte polyploidization and differentiation
► Induction of polyploidization provides a therapeutic strategy for AMKL
Journal: - Volume 150, Issue 3, 3 August 2012, Pages 575–589