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Publication : Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL.

First Author  Wen Q Year  2012
Journal  Cell Volume  150
Issue  3 Pages  575-89
PubMed ID  22863010 Mgi Jnum  J:187884
Mgi Id  MGI:5438688 Doi  10.1016/j.cell.2012.06.032
Citation  Wen Q, et al. (2012) Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL. Cell 150(3):575-89
abstractText  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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