Jean Carlos Lipreri da Silva1, Juan Luiz Coelho-Silva2, Keli Lima1, Hugo Passos Vicari1, Mariana Lazarini3, Leticia Veras Costa-Lotufo1, Fabiola Traina2, João Agostinho Machado-Neto4. 1. Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, CEP 05508-900, São Paulo, SP, Brazil. 2. Department of Medical Imaging, Hematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil. 3. Department of Pharmaceutical Sciences, Federal University of São Paulo, Diadema, Brazil. 4. Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, CEP 05508-900, São Paulo, SP, Brazil. jamachadoneto@usp.br.
Abstract
PURPOSE: Despite great advances that have been made in the understanding of the molecular complexity of acute myeloid leukemia (AML), very little has been translated into new therapies. Here, we set out to investigate the impact of cytoskeleton regulatory genes on clinical outcomes and their potential as therapeutic targets in AML. METHODS: Gene expression and clinical data were retrieved from The Cancer Genome Atlas (TCGA) AML study and used for survival and functional genomics analyses. For pharmacological tests, AML cells were exposed to ezrin (EZR) inhibitors and submitted to several cellular and molecular assays. RESULTS: High EZR expression was identified as an independent marker of worse outcomes in AML patients from the TCGA cohort (p < 0.05). Functional genomics analyses suggested that EZR contributes to responses to stimuli and signal transduction pathways in leukemia cells. EZR pharmacological inhibition with NSC305787 and NSC668394 reduced viability, proliferation, autonomous clonal growth, and cell cycle progression in AML cells (p < 0.05). NSC305787 had a greater potency and efficiency than NSC668394 in leukemia models. At the molecular level, EZR inhibitors reduced EZR, S6 ribosomal protein and 4EBP1 phosphorylation, and induced PARP1 cleavage in AML cells. NSC305787, but not NSC668394, favored a gene network involving cell cycle arrest and apoptosis in Kasumi 1 AML cells. CONCLUSIONS: From our data we conclude that EZR expression may serve as a prognostic factor in AML. Our preclinical findings indicate that ezrin inhibitors may be employed as a putative novel class of AML targeting drugs.
PURPOSE: Despite great advances that have been made in the understanding of the molecular complexity of acute myeloid leukemia (AML), very little has been translated into new therapies. Here, we set out to investigate the impact of cytoskeleton regulatory genes on clinical outcomes and their potential as therapeutic targets in AML. METHODS: Gene expression and clinical data were retrieved from The Cancer Genome Atlas (TCGA) AML study and used for survival and functional genomics analyses. For pharmacological tests, AML cells were exposed to ezrin (EZR) inhibitors and submitted to several cellular and molecular assays. RESULTS: High EZR expression was identified as an independent marker of worse outcomes in AML patients from the TCGA cohort (p < 0.05). Functional genomics analyses suggested that EZR contributes to responses to stimuli and signal transduction pathways in leukemia cells. EZR pharmacological inhibition with NSC305787 and NSC668394 reduced viability, proliferation, autonomous clonal growth, and cell cycle progression in AML cells (p < 0.05). NSC305787 had a greater potency and efficiency than NSC668394 in leukemia models. At the molecular level, EZR inhibitors reduced EZR, S6 ribosomal protein and 4EBP1 phosphorylation, and induced PARP1 cleavage in AML cells. NSC305787, but not NSC668394, favored a gene network involving cell cycle arrest and apoptosis in Kasumi 1 AML cells. CONCLUSIONS: From our data we conclude that EZR expression may serve as a prognostic factor in AML. Our preclinical findings indicate that ezrin inhibitors may be employed as a putative novel class of AML targeting drugs.
Authors: Ildiko Szeverenyi; Andrew J Cassidy; Cheuk Wang Chung; Bernett T K Lee; John E A Common; Stephen C Ogg; Huijia Chen; Shu Yin Sim; Walter L P Goh; Kee Woei Ng; John A Simpson; Li Lian Chee; Goi Hui Eng; Bin Li; Declan P Lunny; Danny Chuon; Aparna Venkatesh; Kian Hoe Khoo; W H Irwin McLean; Yun Ping Lim; E Birgitte Lane Journal: Hum Mutat Date: 2008-03 Impact factor: 4.878
Authors: Timothy J Ley; Christopher Miller; Li Ding; Benjamin J Raphael; Andrew J Mungall; A Gordon Robertson; Katherine Hoadley; Timothy J Triche; Peter W Laird; Jack D Baty; Lucinda L Fulton; Robert Fulton; Sharon E Heath; Joelle Kalicki-Veizer; Cyriac Kandoth; Jeffery M Klco; Daniel C Koboldt; Krishna-Latha Kanchi; Shashikant Kulkarni; Tamara L Lamprecht; David E Larson; Ling Lin; Charles Lu; Michael D McLellan; Joshua F McMichael; Jacqueline Payton; Heather Schmidt; David H Spencer; Michael H Tomasson; John W Wallis; Lukas D Wartman; Mark A Watson; John Welch; Michael C Wendl; Adrian Ally; Miruna Balasundaram; Inanc Birol; Yaron Butterfield; Readman Chiu; Andy Chu; Eric Chuah; Hye-Jung Chun; Richard Corbett; Noreen Dhalla; Ranabir Guin; An He; Carrie Hirst; Martin Hirst; Robert A Holt; Steven Jones; Aly Karsan; Darlene Lee; Haiyan I Li; Marco A Marra; Michael Mayo; Richard A Moore; Karen Mungall; Jeremy Parker; Erin Pleasance; Patrick Plettner; Jacquie Schein; Dominik Stoll; Lucas Swanson; Angela Tam; Nina Thiessen; Richard Varhol; Natasja Wye; Yongjun Zhao; Stacey Gabriel; Gad Getz; Carrie Sougnez; Lihua Zou; Mark D M Leiserson; Fabio Vandin; Hsin-Ta Wu; Frederick Applebaum; Stephen B Baylin; Rehan Akbani; Bradley M Broom; Ken Chen; Thomas C Motter; Khanh Nguyen; John N Weinstein; Nianziang Zhang; Martin L Ferguson; Christopher Adams; Aaron Black; Jay Bowen; Julie Gastier-Foster; Thomas Grossman; Tara Lichtenberg; Lisa Wise; Tanja Davidsen; John A Demchok; Kenna R Mills Shaw; Margi Sheth; Heidi J Sofia; Liming Yang; James R Downing; Greg Eley Journal: N Engl J Med Date: 2013-05-01 Impact factor: 91.245