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_name
Celljournal_title
Cellauthors
Wen Q,Goldenson B,Silver SJ,Schenone M,Dancik V,Huang Z,Wang LZ,Lewis TA,An WF,Li X,Bray MA,Thiollier C,Diebold L,Gilles L,Vokes MS,Moore CB,Bliss-Moreau M,Verplank L,Tolliday NJ,Mishra R,Vemula S,Shi J,Wei Ldoi
10.1016/j.cell.2012.06.032subject
Has Abstractpub_date
2012-08-03 00:00:00pages
575-89issue
3eissn
0092-8674issn
1097-4172pii
S0092-8674(12)00827-6journal_volume
150pub_type
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