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 Mishra; Sasidhar 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

doi:10.1016/j.cell.2012.06.032

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

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Résumé

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.

langue originale	Anglais
Pages (de - à)	575-589
Nombre de pages	15
journal	Cell
Volume	150
Numéro de publication	3
Les DOIs	https://doi.org/10.1016/j.cell.2012.06.032
état	Publié - 3 août 2012

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10.1016/j.cell.2012.06.032

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Wen, Q., Goldenson, B., Silver, S. J., Schenone, M., Dancik, V., Huang, Z., Wang, L. Z., Lewis, T. A., An, W. F., Li, X., Bray, M. A., Thiollier, C., Diebold, L., Gilles, L., Vokes, M. S., Moore, C. B., Bliss-Moreau, M., Verplank, L., Tolliday, N. J., ... 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

@article{aa46ea59087b467f8b802c8b5be0c14a,

title = "Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL",

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.",

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

note = "Funding Information: The authors thank Sandeep Gurbuxani, Alex Minella, and Lou Dor{\'e} for critical reading of the manuscript and Bang Wong for valuable advice on figures of the manuscript. This research was funded by grants from the Samuel Waxman Cancer Research Foundation (J.D.C. and S.I.), the US Israel Binational Science Foundation (to S.I. and J.D.C.), the Leukemia and Lymphoma Society Translational Research Program (J.D.C.), the Children with Leukaemia UK (S.I.), the Israel Science Foundation (S.I.), European Hematology Association (Y.B.), and the Leukemia Research Foundation (Y.B.) and by NIH grants CA101774 (J.D.C.), HL077177 (R.K.), HL075816 (R.K.), and HL081111 (R.K.). Other support included an NIH grant to A.E.C. supporting CellProfiler (GM089652), an NIH grant supporting screening informatics (U54 HG005032), NIH Genomics Based Drug Discovery U54 grants Discovery Pipeline RL1-CA133834, and Driving Medical Projects RL1-GM084437, administratively linked to NIH grants RL1-HG004671 and UL1-DE019585 (A.E.C., P.A.C., V.D., C.B.M., A.M.S., C.A.S., and M.S.). Y.B. is a European Hematology Association Fellow. In vivo treatment of human AMKL samples was supported by Foundation Gustave Roussy and Jos{\'e} Carreras Leukemia Foundation- European Hematology Association (T.M.), CEA-EA, Ligue Nationale Contre le Cancer (F.P.), Association Laurette Fugain (F.P.), Soci{\'e}t{\'e} Fran{\c c}aise d'H{\'e}matologie (B.G., F.P.), and Foundation pour la Recherche M{\'e}dicale (C.T.). The authors would also like to thank Jason Berman, Soheil Meshinchi, Todd Alonzo, and Sommer Castro and the Children's Oncology Group (COG) for their assistance with DS-AMKL specimens. Research with DS-AMKL samples was supported by the Chair's Grant U10 CA98543 (to COG) from the National Cancer Institute (NCI). The project has also been funded in part with Federal funds from the NCI's Initiative for Chemical Genetics under Contract N01-CO-12400. The content of this publication is solely the responsibility of the authors and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. A part of this work was performed by the Northwestern University ChemCore at the Center for Molecular Innovation and Drug Discovery (CMIDD), which is funded by the Chicago Biomedical Consortium with support from The Searle Funds at The Chicago Community Trust. D.G.G. is an employee and shareholder of Merck and Co., Inc. R.J.G. is an employee, shareholder, and board member of Epizyme, Inc. and a member of the SAB of the Michael J. Fox Foundation. ",

year = "2012",

month = aug,

day = "3",

doi = "10.1016/j.cell.2012.06.032",

language = "English",

volume = "150",

pages = "575--589",

journal = "Cell",

issn = "0092-8674",

number = "3",

}

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, Numéro 3, p. 575-589. https://doi.org/10.1016/j.cell.2012.06.032

TY - JOUR

T1 - Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL

AU - Wen, Qiang

AU - Goldenson, Benjamin

AU - Silver, Serena J.

AU - Schenone, Monica

AU - Dancik, Vlado

AU - Huang, Zan

AU - Wang, Ling Zhi

AU - Lewis, Timothy A.

AU - An, W. Frank

AU - Li, Xiaoyu

AU - Bray, Mark Anthony

AU - Thiollier, Clarisse

AU - Diebold, Lauren

AU - Gilles, Laure

AU - Vokes, Martha S.

AU - Moore, Christopher B.

AU - Bliss-Moreau, Meghan

AU - Verplank, Lynn

AU - Tolliday, Nicola J.

AU - Mishra, Rama

AU - Vemula, Sasidhar

AU - Shi, Jianjian

AU - Wei, Lei

AU - Kapur, Reuben

AU - Lopez, Cécile K.

AU - Gerby, Bastien

AU - Ballerini, Paola

AU - Pflumio, Francoise

AU - Gilliland, D. Gary

AU - Goldberg, Liat

AU - Birger, Yehudit

AU - Izraeli, Shai

AU - Gamis, Alan S.

AU - Smith, Franklin O.

AU - Woods, William G.

AU - Taub, Jeffrey

AU - Scherer, Christina A.

AU - Bradner, James E.

AU - Goh, Boon Cher

AU - Mercher, Thomas

AU - Carpenter, Anne E.

AU - Gould, Robert J.

AU - Clemons, Paul A.

AU - Carr, Steven A.

AU - Root, David E.

AU - Schreiber, Stuart L.

AU - Stern, Andrew M.

AU - Crispino, John D.

N1 - Funding Information: The authors thank Sandeep Gurbuxani, Alex Minella, and Lou Doré for critical reading of the manuscript and Bang Wong for valuable advice on figures of the manuscript. This research was funded by grants from the Samuel Waxman Cancer Research Foundation (J.D.C. and S.I.), the US Israel Binational Science Foundation (to S.I. and J.D.C.), the Leukemia and Lymphoma Society Translational Research Program (J.D.C.), the Children with Leukaemia UK (S.I.), the Israel Science Foundation (S.I.), European Hematology Association (Y.B.), and the Leukemia Research Foundation (Y.B.) and by NIH grants CA101774 (J.D.C.), HL077177 (R.K.), HL075816 (R.K.), and HL081111 (R.K.). Other support included an NIH grant to A.E.C. supporting CellProfiler (GM089652), an NIH grant supporting screening informatics (U54 HG005032), NIH Genomics Based Drug Discovery U54 grants Discovery Pipeline RL1-CA133834, and Driving Medical Projects RL1-GM084437, administratively linked to NIH grants RL1-HG004671 and UL1-DE019585 (A.E.C., P.A.C., V.D., C.B.M., A.M.S., C.A.S., and M.S.). Y.B. is a European Hematology Association Fellow. In vivo treatment of human AMKL samples was supported by Foundation Gustave Roussy and José Carreras Leukemia Foundation- European Hematology Association (T.M.), CEA-EA, Ligue Nationale Contre le Cancer (F.P.), Association Laurette Fugain (F.P.), Société Française d'Hématologie (B.G., F.P.), and Foundation pour la Recherche Médicale (C.T.). The authors would also like to thank Jason Berman, Soheil Meshinchi, Todd Alonzo, and Sommer Castro and the Children's Oncology Group (COG) for their assistance with DS-AMKL specimens. Research with DS-AMKL samples was supported by the Chair's Grant U10 CA98543 (to COG) from the National Cancer Institute (NCI). The project has also been funded in part with Federal funds from the NCI's Initiative for Chemical Genetics under Contract N01-CO-12400. The content of this publication is solely the responsibility of the authors and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. A part of this work was performed by the Northwestern University ChemCore at the Center for Molecular Innovation and Drug Discovery (CMIDD), which is funded by the Chicago Biomedical Consortium with support from The Searle Funds at The Chicago Community Trust. D.G.G. is an employee and shareholder of Merck and Co., Inc. R.J.G. is an employee, shareholder, and board member of Epizyme, Inc. and a member of the SAB of the Michael J. Fox Foundation.

PY - 2012/8/3

Y1 - 2012/8/3

N2 - 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.

AB - 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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