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Identification of Regulators of Polyploidization Presents Therapeutic Targets for Treatment of AMKL |
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| Authors: | Qiang Wen Benjamin Goldenson Serena J Silver Monica Schenone Vlado Dancik Zan Huang Ling-Zhi Wang Timothy A Lewis W Frank An Xiaoyu Li Mark-Anthony Bray Clarisse Thiollier Lauren Diebold Laure Gilles Martha S Vokes Christopher B Moore Meghan Bliss-Moreau Lynn Verplank Nicola J Tolliday Rama Mishra Sasidhar Vemula Jianjian Shi Lei Wei Reuben Kapur Cécile K Lopez Bastien Gerby Paola Ballerini Francoise Pflumio D Gary Gilliland Liat Goldberg Yehudit Birger Shai Izraeli Alan S Gamis Franklin O Smith William G Woods Jeffrey Taub Christina A Scherer James E Bradner Boon-Cher Goh Thomas Mercher |
| Institution: | 1 Division of Hematology/Oncology, Northwestern University, Chicago, IL 60611, USA 2 Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA 3 Cancer Science Institute, National University of Singapore 117599, Singapore 4 Institut Gustave Roussy, INSERM U985, 94800 Villejuif, France 5 Center for Molecular Innovation and Drug Discovery (CMIDD), Evanston, Northwestern University, Chicago, IL 60208, USA 6 Department of Pediatrics, Indiana University, Indianapolis, IN 46202, USA 7 INSERM UMR967, Institut de radiobiologie cellulaire et moléculaire, CEA-EA 92265 Fontenay-aux-Roses, France 8 Hôpital Trousseau, AP-HP, 75571 Paris, France 9 Merck, West Point, PA 19446, USA 10 Sheba Medical Center, Tel Aviv University, Ramat Gan 52621, Israel 11 Children's Mercy Hospital and Clinics, Kansas City, MO 64108, USA 12 University of Cincinnati Cancer Institute, Cincinnati, OH 45229, USA 13 Aflac Cancer Center, Children's Healthcare of Atlanta and Emory University, Atlanta, GA 30322, USA 14 Children's Hospital of Michigan, Detroit, MI 48201, USA 15 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA |
| Abstract: | 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. |
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