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.
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We thank T. Sato and M. Kurokawa (University of Tokyo) for providing plasmid constructs and detailed procedures for Evi1 overexpression in mouse hematopoietic cells. We also thank J.F. Clark (University of Cincinnati) for advice on the use of cyclocreatine in vivo. This research was supported with grants from the US National Cancer Institute (NCI) (NIH 1R35 CA210030-01 (K. Stegmaier) and R37 CA72614 (K. Shannon)), the Stand-up-to-Cancer Program (K. Stegmaier); the Bridge Project, a collaboration between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber–Harvard Cancer Center (DF–HCC) (K. Stegmaier and M.T.H.) and the Koch Institute Cancer Center Support (NCI grant P30-CA14051; M.T.H.), and with support from the Cubans Curing Children's Cancers (4C's Fund) (K. Stegmaier). A.P. is a recipient of support from the ATIP–AVENIR and LNCC French research programs, the EHA research grant for a Non-Clinical Advanced fellow, and is supported by the St. Louis Association for leukemia research. K. Stegmaier is an LLS Scholar. A.P., N.F. and I.B.-S. were awarded the 'Prix Jeune Chercheur' from the Bettencourt Foundation and the Franco-American Exchange Prize from Philippe Foundation Inc.
The authors declare no competing financial interests.
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Fenouille, N., Bassil, C., Ben-Sahra, I. et al. The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia. Nat Med 23, 301–313 (2017). https://doi.org/10.1038/nm.4283
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