Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL.
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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. |
Year of Publication | 2012
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Journal | Cell
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Volume | 150
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Issue | 3
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Pages | 575-89
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Date Published | 2012 Aug 03
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ISSN | 1097-4172
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URL | |
DOI | 10.1016/j.cell.2012.06.032
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PubMed ID | 22863010
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PubMed Central ID | PMC3613864
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Grant list | UL1-DE019585 / DE / NIDCR NIH HHS / United States
R56 HL075816 / HL / NHLBI NIH HHS / United States
R01 HL081111 / HL / NHLBI NIH HHS / United States
R01 HL075816 / HL / NHLBI NIH HHS / United States
HL077177 / HL / NHLBI NIH HHS / United States
U54 HG005032 / HG / NHGRI NIH HHS / United States
R01 CA101774 / CA / NCI NIH HHS / United States
UL1 DE019585 / DE / NIDCR NIH HHS / United States
N01--CO-12400 / CO / NCI NIH HHS / United States
CA101774 / CA / NCI NIH HHS / United States
RL1-GM084437 / GM / NIGMS NIH HHS / United States
R01 GM089652 / GM / NIGMS NIH HHS / United States
P30 DK056465 / DK / NIDDK NIH HHS / United States
RL1-CA133834 / CA / NCI NIH HHS / United States
P01 HL085098 / HL / NHLBI NIH HHS / United States
RL1 GM084437 / GM / NIGMS NIH HHS / United States
RL1-HG004671 / HG / NHGRI NIH HHS / United States
U10 CA098543 / CA / NCI NIH HHS / United States
HL075816 / HL / NHLBI NIH HHS / United States
GM089652 / GM / NIGMS NIH HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
R01 HL077177 / HL / NHLBI NIH HHS / United States
RL1 HG004671 / HG / NHGRI NIH HHS / United States
RL1 CA133834 / CA / NCI NIH HHS / United States
HL081111 / HL / NHLBI NIH HHS / United States
U10 CA98543 / CA / NCI NIH HHS / United States
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