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

• Type of Material: Article
• Authors: Qiang Wen, Northwestern University; Benjamin Goldenson, Northwestern University; Serena J. Silver, Broad Inst Harvard & MIT; Monica Schenone, Broad Inst Harvard & MIT; Vladimir Dancik, Broad Inst Harvard & MIT; Zan Huang, Northwestern University; Ling-Zhi Wang, Natl Univ Singapore; Timothy Lewis, Broad Inst Harvard & MIT; W. Frank An, Broad Inst Harvard & MIT; Xiaoyu Li, Broad Inst Harvard & MIT; Mark-Anthony Bray, Broad Inst Harvard & MIT; Clarisse Thiollier, Inst Gustave Roussy; Lauren Diebold, Northwestern University; Laure Gilles, Northwestern University; Martha S. Vokes, Broad Inst Harvard & MIT; Christopher B. Moore, Broad Inst Harvard & MIT; Meghan Bliss-Moreau, Broad Inst Harvard & MIT; Lynn VerPlank, Broad Inst Harvard & MIT; Nicola J. Tolliday, Broad Inst Harvard & MIT; William G Woods, Emory University
• Language: English
• Date: 2012-08-03
• Publisher: IOS Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cell.2012.06.032
• Title of Journal or Parent Work: Analytical Cellular Pathology / Cellular Oncology
• ISSN: 1570-5870
• Volume: 150
• Issue: 3
• Start Page: 575
• End Page: 589
• Grant/Funding Information: 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).; 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.; The project has also been funded in part with Federal funds from the NCI’s Initiative for Chemical Genetics under Contract N01-CO-12400.
• Keywords: B KINASE; PHOSPHORYLATION; Life Sciences & Biomedicine; AURORA-A KINASE; Cell Biology; CELL-CYCLE; VALIDATION; ACUTE MEGAKARYOCYTIC LEUKEMIA; ACUTE MEGAKARYOBLASTIC LEUKEMIA; DOWN-SYNDROME; MEGAKARYOPOIESIS; Science & Technology; Biochemistry & Molecular Biology; INHIBITOR MLN8237
• Research Categories: Health Sciences, Oncology; Health Sciences, General

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.