Integrative screening approach identifies regulators of polyploidization and targets for acute megakaryocytic leukemia
| Autor: | Wen, Qiang, Goldenson, Benjamin, Silver, Serena J., Schenone, Monica, Dancik, Vladimir, Huang, Zan, Wang, Ling-Zhi, Lewis, Timothy, An, W. Frank, Li, Xiaoyu, Bray, Mark-Anthony, Thiollier, Clarisse, Diebold, Lauren, Gilles, Laure, Vokes, Martha S., Moore, Christopher B., Bliss-Moreau, Meghan, VerPlank, Lynn, Tolliday, Nicola J., Mishra, Rama, Vemula, Sasidhar, Shi, Jianjian, Wei, Lei, Kapur, Reuben, Lopez, Cécile K., Gerby, Bastien, Ballerini, Paola, Pflumio, Francoise, Gilliland, D. Gary, Goldberg, Liat, Birger, Yehudit, Izraeli, Shai, Gamis, Alan S., Smith, Franklin O., Woods, William G., Taub, Jeffrey, Scherer, Christina A., Bradner, James, Goh, Boon-Cher, Mercher, Thomas, Carpenter, Anne E., Gould, Robert J., Clemons, Paul A., Carr, Steven A., Root, David E., Schreiber, Stuart L., Stern, Andrew M., Crispino, John D. |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
rho-Associated Kinases
food and beverages Cell Differentiation Azepines Protein Serine-Threonine Kinases Article Mice Inbred C57BL Polyploidy Small Molecule Libraries Mice Pyrimidines Aurora Kinases Leukemia Megakaryoblastic Acute 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine Drug Discovery Animals Humans Protein Interaction Maps Megakaryocytes Aurora Kinase A Cell Proliferation |
| Popis: | 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. We found that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. A broadly applicable, highly integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora A kinase (AURKA), which has not been studied extensively in megakaryocytes. Moreover, we discovered that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in AMKL blasts and displayed potent anti-AMKL activity in vivo. This research provides the rationale to support clinical trials of MLN8237 and other inducers of polyploidization in AMKL. Finally, we have identified five networks of kinases that regulate the switch to polyploidy. |
| Databáze: | OpenAIRE |
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