Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia
- Stefan P. Glaser1,2,
- Erinna F. Lee1,2,
- Evelyn Trounson1,
- Philippe Bouillet1,2,
- Andrew Wei3,
- W. Douglas Fairlie1,2,
- David J. Izon4,
- Johannes Zuber5,6,
- Amy R. Rappaport5,7,
- Marco J. Herold1,2,
- Warren S. Alexander1,2,
- Scott W. Lowe5,7,8,
- Lorraine Robb1,2 and
- Andreas Strasser1,2,9
- 1The Walter and Eliza Hall Institute, Parkville, Melbourne, Victoria 3052, Australia;
- 2Department of Medical Biology, The University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia;
- 3The Australian Centre for Blood Diseases, Alfred Hospital and Monash University, Melbourne, Victoria 3004, Australia;
- 4St. Vincent's Institute, Fitzroy, Victoria 3065, Australia;
- 5Cold Spring Harbor Laboratories, Cold Spring Harbor, New York 11724, USA;
- 6Research Institute of Molecular Pathology (IMP), A-1030 Vienna, Austria;
- 7Watson School of Biological Sciences, Cold Spring Harbor, New York 11724, USA;
- 8Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
Abstract
Acute myeloid leukemia (AML) frequently relapses after initial treatment. Drug resistance in AML has been attributed to high levels of the anti-apoptotic Bcl-2 family members Bcl-xL and Mcl-1. Here we report that removal of Mcl-1, but not loss or pharmacological blockade of Bcl-xL, Bcl-2, or Bcl-w, caused the death of transformed AML and could cure disease in AML-afflicted mice. Enforced expression of selective inhibitors of prosurvival Bcl-2 family members revealed that Mcl-1 is critical for survival of human AML cells. Thus, targeting of Mcl-1 or regulators of its expression may be a useful strategy for the treatment of AML.
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Footnotes
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↵9 Corresponding author.
E-mail strasser{at}wehi.edu.au.
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.182980.111.
- Received November 9, 2011.
- Accepted December 14, 2011.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press
