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Nat Med. 2017 Mar;23(3):301-313. doi: 10.1038/nm.4283. Epub 2017 Feb 13.

The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia.

Author information

1
Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
2
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
3
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
4
Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
5
Bioinformatics Graduate Program, Boston University, Boston, Massachusetts, USA.
6
Department of Medicine, University of California San Francisco, San Francisco, California, USA.
7
Internal Medicine Hematology-Oncology, University of Michigan, Ann Arbor, Michigan, USA.
8
Université Côte d'Azur, UMR INSERM U1065, C3M, Nice, France.
9
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
10
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, New York, USA.
11
Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA.
12
INSERM UMR 944, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris, France.

Abstract

Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens.

PMID:
28191887
PMCID:
PMC5540325
DOI:
10.1038/nm.4283
[Indexed for MEDLINE]
Free PMC Article

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