Inhibition of Mitochondrial Translation As a Therapeutic Strategy for Human Acute Myeloid Leukemia

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2011 Nov 19

PMID 22094260

Citations 325

Authors

Marko Skrtic

Shrivani Sriskanthadevan

Bozhena Jhas

Marinella Gebbia

Xiaoming Wang

Zezhou Wang

Rose Hurren

Yulia Jitkova

Marcela Gronda

Neil MacLean

Courteney K Lai

Yanina Eberhard

Justyna Bartoszko

Paul Spagnuolo

Angela C Rutledge

Alessandro Datti

Troy Ketela

Jason Moffat

Brian H Robinson

Jessie H Cameron

Jeffery Wrana

Connie J Eaves

Mark D Minden

Jean C Y Wang

John E Dick

Keith Humphries

Corey Nislow

Guri Giaever

Aaron D Schimmer

Affiliations

Soon will be listed here.

Abstract

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.

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