Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia.


Skrti, Marko; Sriskanthadevan, Shrivani; Jhas, Bozhena; Gebbia, Marinella; Wang, Xiaoming; Wang, Zezhou; Hurren, Rose; Jitkova, Yulia; Gronda, Marcela; Maclean, Neil; Lai, Courteney K; Eberhard, Yanina; Bartoszko, Justyna; Spagnuolo, Paul; Rutledge, Angela C; Datti, Alessandro; Ketela, Troy; Moffat, Jason; Robinson, Brian H; Cameron, Jessie H; Wrana, Jeffery; Eaves, Connie J; Minden, Mark D; Wang, Jean C Y; Dick, John E; Humphries, Keith; Nislow, Corey; Giaever, Guri; Schimmer, Aaron D

Publication Year 2011
Journal Cancer Cell
Pages 674-688
Volume 20
Issue 5
PMID 22094260.0
PMCID PMC3221282
DOI 10.1016/j.ccr.2011.10.015

To identify FDA-approved agents targeting leukemic cells, we performed a chemical screen on two human leukemic cell lines and identified the antimicrobial tigecycline. A genome-wide screen in yeast identified mitochondrial translation inhibition as the mechanism of tigecycline-mediated lethality. Tigecycline selectively killed leukemia stem and progenitor cells compared to their normal counterparts and also showed antileukemic activity in mouse models of human leukemia. ShRNA-mediated knockdown of EF-Tu mitochondrial translation factor in leukemic cells reproduced the antileukemia activity of tigecycline. These effects were derivative of mitochondrial biogenesis that, together with an increased basal oxygen consumption, proved to be enhanced in AML versus normal hematopoietic cells and were also important for their difference in tigecycline sensitivity. 2011 Elsevier Inc. All rights reserved.