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Author Notes:

Corresponding Authors: John Crispino, PhD, Northwestern University, Division of Hematology/Oncology, 303 East Superior Street, Lurie 5-113, Chicago, IL 60611, j-crispino@northwestern.edu, Andrew Stern, PhD, Broad Institute of Harvard and MIT, 7 Cambridge Center, Room 2012, Cambridge, MA 02142, astern@broadinstitute.org.

For a full list of authors, please see full article.

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.

YB 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 (TM), CEA-EA, Ligue Nationale Contre le Cancer (FP), Association Laurette Fugain (FP), Société Française d’Hématologie (BG, FP), Foundation pour la Recherche Médicale (CT).

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 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.

Subjects:

Research Funding:

This research was funded by grants from the Samuel Waxman Cancer Research Foundation (JDC and SI), the US Israel Binational Science Foundation (to SI and JC), the Leukemia and Lymphoma Society Translational Research Program (JDC), the Children with Leukaemia UK (SI), the Leukemia Research Foundation (YB), and by NIH grants CA101774 (JDC), HL077177 (RK), HL075816 (RK) and HL081111 (RK).

Other support included an NIH grant to AEC 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 (AEC, PAC, VD, CM, AS, CAS, and MS).

The project has also been funded in part with Federal funds from the NCI’s Initiative for Chemical Genetics under Contract N01-CO-12400.

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.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology
  • ACUTE MEGAKARYOBLASTIC LEUKEMIA
  • ACUTE MEGAKARYOCYTIC LEUKEMIA
  • AURORA-A KINASE
  • INHIBITOR MLN8237
  • DOWN-SYNDROME
  • CELL-CYCLE
  • B KINASE
  • PHOSPHORYLATION
  • MEGAKARYOPOIESIS
  • VALIDATION

Identification of Regulators of Polyploidization Presents Therapeutic Targets for Treatment of AMKL/Post-Print Title: Integrative screening approach identifies regulators of polyploidization and targets for acute megakaryocytic leukemia

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Journal Title:

Analytical Cellular Pathology / Cellular Oncology

Volume:

Volume 150, Number 3

Publisher:

, Pages 575-589

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2012 Elsevier Inc. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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