Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL

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 MishraSasidhar 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, Anne E. Carpenter, Robert J. Gould, Paul A. Clemons, Steven A. Carr, David E. Root, Stuart L. Schreiber, Andrew M. Stern, John D. Crispino

Research output: Contribution to journalArticle

80 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)575-589
Number of pages15
JournalCell
Volume150
Issue number3
DOIs
StatePublished - Aug 3 2012

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Leukemia, Megakaryoblastic, Acute
Aurora Kinase A
Polyploidy
Megakaryocytes
Small Interfering RNA
Screening
Phosphotransferases
Therapeutics
Switches
Mitosis
Proteomics
Apoptosis
Molecules
Clinical Trials
MLN 8237
2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Wen, Q., Goldenson, B., Silver, S. J., Schenone, M., Dancik, V., Huang, Z., ... Crispino, J. D. (2012). Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL. Cell, 150(3), 575-589. https://doi.org/10.1016/j.cell.2012.06.032

Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL. / Wen, Qiang; Goldenson, Benjamin; Silver, Serena J.; Schenone, Monica; Dancik, Vlado; Huang, Zan; Wang, Ling Zhi; Lewis, Timothy A.; An, W. Frank; Li, Xiaoyu; Bray, Mark Anthony; Thiollier, Clarisse; Diebold, Lauren; Gilles, Laure; Vokes, Martha S.; Moore, Christopher B.; Bliss-Moreau, Meghan; Verplank, Lynn; Tolliday, Nicola J.; Mishra, Rama; Vemula, Sasidhar; Shi, Jianjian; Wei, Lei; Kapur, Reuben; Lopez, Cécile K.; Gerby, Bastien; Ballerini, Paola; Pflumio, Francoise; Gilliland, D. Gary; Goldberg, Liat; Birger, Yehudit; Izraeli, Shai; Gamis, Alan S.; Smith, Franklin O.; Woods, William G.; Taub, Jeffrey; Scherer, Christina A.; Bradner, James E.; Goh, Boon Cher; Mercher, Thomas; Carpenter, Anne E.; Gould, Robert J.; Clemons, Paul A.; Carr, Steven A.; Root, David E.; Schreiber, Stuart L.; Stern, Andrew M.; Crispino, John D.

In: Cell, Vol. 150, No. 3, 03.08.2012, p. 575-589.

Research output: Contribution to journalArticle

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, L, Kapur, R, Lopez, CK, Gerby, B, Ballerini, P, Pflumio, F, Gilliland, DG, Goldberg, L, Birger, Y, Izraeli, S, Gamis, AS, Smith, FO, Woods, WG, Taub, J, Scherer, CA, Bradner, JE, Goh, BC, Mercher, T, Carpenter, AE, Gould, RJ, Clemons, PA, Carr, SA, Root, DE, Schreiber, SL, Stern, AM & Crispino, JD 2012, 'Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL', Cell, vol. 150, no. 3, pp. 575-589. https://doi.org/10.1016/j.cell.2012.06.032
Wen Q, Goldenson B, Silver SJ, Schenone M, Dancik V, Huang Z et al. Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL. Cell. 2012 Aug 3;150(3):575-589. https://doi.org/10.1016/j.cell.2012.06.032
Wen, Qiang ; Goldenson, Benjamin ; Silver, Serena J. ; Schenone, Monica ; Dancik, Vlado ; Huang, Zan ; Wang, Ling Zhi ; Lewis, Timothy A. ; An, W. Frank ; Li, Xiaoyu ; Bray, Mark Anthony ; Thiollier, Clarisse ; Diebold, Lauren ; Gilles, Laure ; Vokes, Martha S. ; Moore, Christopher B. ; Bliss-Moreau, Meghan ; Verplank, Lynn ; Tolliday, Nicola J. ; Mishra, Rama ; Vemula, Sasidhar ; Shi, Jianjian ; Wei, Lei ; Kapur, Reuben ; Lopez, Cécile K. ; Gerby, Bastien ; Ballerini, Paola ; Pflumio, Francoise ; Gilliland, D. Gary ; Goldberg, Liat ; Birger, Yehudit ; Izraeli, Shai ; Gamis, Alan S. ; Smith, Franklin O. ; Woods, William G. ; Taub, Jeffrey ; Scherer, Christina A. ; Bradner, James E. ; Goh, Boon Cher ; Mercher, Thomas ; Carpenter, Anne E. ; Gould, Robert J. ; Clemons, Paul A. ; Carr, Steven A. ; Root, David E. ; Schreiber, Stuart L. ; Stern, Andrew M. ; Crispino, John D. / Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL. In: Cell. 2012 ; Vol. 150, No. 3. pp. 575-589.
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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.",
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AU - Wei, Lei

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AU - Ballerini, Paola

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AU - Gilliland, D. Gary

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AU - Birger, Yehudit

AU - Izraeli, Shai

AU - Gamis, Alan S.

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AU - Woods, William G.

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AU - Bradner, James E.

AU - Goh, Boon Cher

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