Title of article :
Identification of Regulators of Polyploidization Presents Therapeutic Targets for Treatment of AMKL
Author/Authors :
Qiang Wen، نويسنده , , Benjamin Goldenson، نويسنده , , Serena J. Silver، نويسنده , , Monica Schenone، نويسنده , , Vlado Dancik، نويسنده , , Zan Huang، نويسنده , , Ling-Zhi Wang، نويسنده , , Timothy A. Lewis، نويسنده , , W. Frank An، نويسنده , , XIAOYU LI، نويسنده , , Mark-Anthony Bray، نويسنده , , Clarisse Thiollier، نويسنده , , Lauren Diebold، نويسنده , , Laure Gilles، نويسنده , , Martha S. Vokes، نويسنده , , Christopher B. Moore، نويسنده , , Meghan Bliss-Moreau، نويسنده , , Lynn VerPlank، نويسنده , , Nicola J. Tolliday، نويسنده , , Rama Mishra، نويسنده , , et al.، نويسنده ,
Issue Information :
هفته نامه با شماره پیاپی سال 2012
Pages :
15
From page :
575
To page :
589
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.
Journal title :
CELL
Serial Year :
2012
Journal title :
CELL
Record number :
1021306
Link To Document :
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