Identification of Regulators of Polyploidization Presents Therapeutic Targets for Treatment of AMKL

被引：133

作者：

Wen, Qiang ^{[2
]}

Goldenson, Benjamin ^{[2
]}

Silver, Serena J. ^{[1
]}

Schenone, Monica ^{[1
]}

Dancik, Vlado ^{[1
]}

Huang, Zan ^{[2
]}

Wang, Ling-Zhi ^{[3
]}

Lewis, Timothy A. ^{[1
]}

An, W. Frank ^{[1
]}

Li, Xiaoyu ^{[1
]}

Bray, Mark-Anthony ^{[1
]}

Thiollier, Clarisse ^{[4
]}

Diebold, Lauren ^{[2
]}

Gilles, Laure ^{[2
]}

Vokes, Martha S. ^{[1
]}

Moore, Christopher B. ^{[1
]}

Bliss-Moreau, Meghan ^{[1
]}

VerPlank, Lynn ^{[1
]}

Tolliday, Nicola J. ^{[1
]}

Mishra, Rama ^{[5
,6
]}

Vemula, Sasidhar ^{[7
]}

Shi, Jianjian ^{[7
]}

Wei, Lei ^{[7
]}

Kapur, Reuben ^{[7
]}

Lopez, Cecile K. ^{[4
]}

Gerby, Bastien ^{[8
]}

Ballerini, Paola ^{[9
]}

Pflumio, Francoise ^{[8
]}

Gilliland, D. Gary ^{[10
]}

Goldberg, Liat ^{[11
]}

Birger, Yehudit ^{[11
]}

Izraeli, Shai ^{[11
]}

Gamis, Alan S. ^{[12
]}

Smith, Franklin O. ^{[13
]}

Woods, William G. ^{[14
,15
]}

Taub, Jeffrey ^{[16
]}

Scherer, Christina A. ^{[1
]}

Bradner, James E. ^{[1
,17
]}

Goh, Boon-Cher ^{[3
]}

Mercher, Thomas ^{[4
]}

Carpenter, Anne E. ^{[1
]}

Gould, Robert J. ^{[1
]}

Clemons, Paul A. ^{[1
]}

Carr, Steven A. ^{[1
]}

Root, David E. ^{[1
]}

Schreiber, Stuart L. ^{[1
]}

Stern, Andrew M. ^{[1
]}

Crispino, John D. ^{[2
]}

机构：

[1] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[2] Northwestern Univ, Div Hematol Oncol, Chicago, IL 60611 USA

[3] Natl Univ Singapore, Canc Sci Inst, Singapore 117599, Singapore

[4] Inst Gustave Roussy, INSERM, U985, F-94805 Villejuif, France

[5] CMIDD, Evanston, IL USA

[6] Northwestern Univ, Chicago, IL 60208 USA

[7] Indiana Univ, Dept Pediat, Indianapolis, IN 46202 USA

[8] INSERM, CEA, Inst Radiobiol Cellulaire & Mol, EA 92265,UMR967, Fontenay Aux Roses, France

[9] Hop Trousseau, AP HP, F-75571 Paris, France

[10] Merck Sharp & Dohme Ltd, West Point, PA 19446 USA

[11] Tel Aviv Univ, Sheba Med Ctr, IL-52621 Ramat Gan, Israel

[12] Childrens Mercy Hosp & Clin, Kansas City, MO 64108 USA

[13] Univ Cincinnati, Inst Canc, Cincinnati, OH 45229 USA

[14] Childrens Healthcare Atlanta, Aflac Canc Ctr, Atlanta, GA 30322 USA

[15] Emory Univ, Atlanta, GA 30322 USA

[16] Childrens Hosp Michigan, Detroit, MI 48201 USA

[17] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

来源：

CELL | 2012年 / 150卷 / 03期

基金：

以色列科学基金会;

关键词：

ACUTE MEGAKARYOBLASTIC LEUKEMIA; ACUTE MEGAKARYOCYTIC LEUKEMIA; AURORA-A KINASE; INHIBITOR MLN8237; DOWN-SYNDROME; CELL-CYCLE; B KINASE; PHOSPHORYLATION; MEGAKARYOPOIESIS; VALIDATION;

D O I：

10.1016/j.cell.2012.06.032

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：575 / 589

页数：15

共 41 条

[1] Regulation of megakaryocyte maturation and platelet formation [J].

Bluteau, D. ;

Lordier, L. ;

Di Stefano, A. ;

Chang, Y. ;

Raslova, H. ;

Debili, N. ;

Vainchenker, W. .

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2009, 7 :227-234

[2] The cellular geography of aurora kinases [J].

Carmena, M ;

Earnshaw, WC .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2003, 4 (11) :842-854

[3] CellProfiler: image analysis software for identifying and quantifying cell phenotypes [J].

Carpenter, Anne E. ;

Jones, Thouis Ray ;

Lamprecht, Michael R. ;

Clarke, Colin ;

Kang, In Han ;

Friman, Ola ;

Guertin, David A. ;

Chang, Joo Han ;

Lindquist, Robert A. ;

Moffat, Jason ;

Golland, Polina ;

Sabatini, David M. .

GENOME BIOLOGY, 2006, 7 (10)

[4] Aurora-A Kinase Is Essential for Bipolar Spindle Formation and Early Development [J].

Cowley, Dale O. ;

Rivera-Perez, Jaime A. ;

Schliekelman, Mark ;

He, Yizhou Joseph ;

Oliver, Trudy G. ;

Lu, Lucy ;

O'Quinn, Ryan ;

Salmon, E. D. ;

Magnuson, Terry ;

Van Dyke, Terry .

MOLECULAR AND CELLULAR BIOLOGY, 2009, 29 (04) :1059-1071

[5] Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells [J].

D'Alise, Anna Morena ;

Amabile, Giovanni ;

Iovino, Mariangela ;

Di Giorgio, Francesco Paolo ;

Bartiromo, Marta ;

Sessa, Fabio ;

Villa, Fabrizio ;

Musacchio, Andrea ;

Cortese, Riccardo .

MOLECULAR CANCER THERAPEUTICS, 2008, 7 (05) :1140-1149

[6] Aurora Kinase-A Regulates Microtubule Organizing Center (MTOC) Localization, Chromosome Dynamics, and Histone-H3 Phosphorylation in Mouse Oocytes [J].

Ding, Jun ;

Swain, Jason E. ;

Smith, Gary D. .

MOLECULAR REPRODUCTION AND DEVELOPMENT, 2011, 78 (02) :80-90

[7] A small molecule-kinase interaction map for clinical kinase inhibitors [J].

Fabian, MA ;

Biggs, WH ;

Treiber, DK ;

Atteridge, CE ;

Azimioara, MD ;

Benedetti, MG ;

Carter, TA ;

Ciceri, P ;

Edeen, PT ;

Floyd, M ;

Ford, JM ;

Galvin, M ;

Gerlach, JL ;

Grotzfeld, RM ;

Herrgard, S ;

Insko, DE ;

Insko, MA ;

Lai, AG ;

Lélias, JM ;

Mehta, SA ;

Milanov, ZV ;

Velasco, AM ;

Wodicka, LM ;

Patel, HK ;

Zarrinkar, PP ;

Lockhart, DJ .

NATURE BIOTECHNOLOGY, 2005, 23 (03) :329-336

[8] Anovel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma [J].

Goerguen, Guellue ;

Calabrese, Elisabetta ;

Hideshima, Teru ;

Ecsedy, Jeffrey ;

Perrone, Giulia ;

Mani, Mala ;

Ikeda, Hiroshi ;

Bianchi, Giada ;

Hu, Yiguo ;

Cirstea, Diana ;

Santo, Loredana ;

Tai, Yu-Tzu ;

Nahar, Sabikun ;

Zheng, Mei ;

Bandi, Madhavi ;

Carrasco, Ruben D. ;

Raje, Noopur ;

Munshi, Nikhil ;

Richardson, Paul ;

Anderson, Kenneth C. .

BLOOD, 2010, 115 (25) :5202-5213

[9] Roles of focal adhesion kinase (FAK) in megakaryopoiesis and platelet function:: studies using a megakaryocyte lineage-specific FAK knockout [J].

Hitchcock, Ian S. ;

Fox, Norma E. ;

Prevost, Nicolas ;

Sear, Katherine ;

Shattil, Sanford J. ;

Kaushansky, Kenneth .

BLOOD, 2008, 111 (02) :596-604

[10] Inhibition of Rho-kinase-induced myristoylated alanine-rich C kinase substrate (MARCKS) phosphorylation in human neuronal cells by H-1152, a novel and specific Rho-kinase inhibitor [J].

Ikenoya, M ;

Hidaka, H ;

Hosoya, T ;

Suzuki, M ;

Yamamoto, N ;

Sasaki, Y .

JOURNAL OF NEUROCHEMISTRY, 2002, 81 (01) :9-16

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