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

Nature Medicine volume 23, pages 301–313 (2017)Cite this article

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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.

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Figure 1: EVI1 overexpression imparts new metabolic dependencies on AML cells.
Figure 2: EVI1-positive cells have high expression of CKMT1 and are dependent on CKMT1 for survival.
Figure 3: EVI1-mediated downregulation of RUNX1 expression promotes CKMT1 expression.
Figure 4: Blockade of the arginine–creatine pathway after CKMT1 inhibition impairs both mitochondrial respiration and ATP production in cells from patients with EVI1-positive AML.
Figure 5: Inhibition of the creatine kinase pathway alters the viability of AML cells derived from individuals with EVI-1-positive AML via cell cycle blockade and apoptosis induction.
Figure 6: CKMT1 knockdown preferentially impairs development of EVI1-positive human and mouse myeloid leukemias without affecting the viability of healthy progenitor cells.

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Acknowledgements

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.

Author information

Author notes

  1. Nina Fenouille and Christopher F Bassil: These authors contributed equally to this work.

  2. Michael T Hemann, Alexandre Puissant and Kimberly Stegmaier: These authors jointly directed this work.

Authors and Affiliations

  1. Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Nina Fenouille, Azucena Ramos & Michael T Hemann

  2. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Christopher F Bassil, Lina Benajiba, Gabriela Alexe, Yana Pikman, Amy S Conway, Alexandre Puissant & Kimberly Stegmaier

  3. Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts, USA

    Issam Ben-Sahra

  4. Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Gabriela Alexe & Kimberly Stegmaier

  5. Bioinformatics Graduate Program, Boston University, Boston, Massachusetts, USA

    Gabriela Alexe

  6. Department of Medicine, University of California San Francisco, San Francisco, California, USA

    Michael R Burgess

  7. Internal Medicine Hematology–Oncology, University of Michigan, Ann Arbor, Michigan, USA

    Qing Li

  8. Université Côte d'Azur, UMR INSERM U1065, C3M, Nice, France

    Frédéric Luciano & Patrick Auberger

  9. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Ilene Galinsky, Daniel J DeAngelo & Richard M Stone

  10. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, New York, USA

    Yi Zhang & Archibald S Perkins

  11. Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA

    Kevin Shannon

  12. INSERM UMR 944, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris, France

    Alexandre Puissant

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  1. Nina Fenouille
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Contributions

N.F. and C.F.B. contributed equally to the manuscript as joint first authors. N.F. and C.F.B. developed the study, established conditions for in vivo and in vitro experiments, acquired and analyzed the data, and wrote the manuscript; I.B.-S. designed and performed the metabolism-related experiments; L.B., A.R., Y.P., A.S.C. and F.L. designed, performed, and analyzed the in vivo experiments; Q.L., M.R.B. and K. Shannon revised the manuscript and provided NrasG12D and NrasG12D + Evi1 mouse models and methodology for in vivo functional analyses; G.A. revised the manuscript and performed statistical analysis, biostatistics, and computational analysis of the RNA sequencing, the publicly available patient sample cohorts, and the shRNA screening experiments; A.S.P. and Y.Z. provided reagents and ChIP-seq data for the ChIP–qPCR experiments performed on endogenous mouse Evi1; I.G., D.J.D. and R.M.S. provided patient samples and revised the manuscript; P.A. revised the manuscript; M.T.H., A.P. and K Stegmaier contributed equally to this work as joint senior authors; M.T.H., A.P. and K. Stegmaier supervised the study, wrote and revised the manuscript, designed the in vitro and in vivo experiments, analyzed the data and provided funding for the study.

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Correspondence to Kimberly Stegmaier.

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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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