title: The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia.
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.
authors.affiliation: Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Fenouille
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Bassil
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Issam
authors.initials: I
authors.lastname: Ben-Sahra
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Benajiba
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Bioinformatics Graduate Program, Boston University, Boston, Massachusetts, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Alexe
authors.affiliation: Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Azucena
authors.initials: A
authors.lastname: Ramos
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yana
authors.initials: Y
authors.lastname: Pikman
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Conway
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Burgess
authors.affiliation: Internal Medicine Hematology-Oncology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Université Côte d'Azur, UMR INSERM U1065, C3M, Nice, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Luciano
authors.affiliation: Université Côte d'Azur, UMR INSERM U1065, C3M, Nice, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ilene
authors.initials: I
authors.lastname: Galinsky
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, New York, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, New York, USA.
authors.forename: Archibald S
authors.initials: AS
authors.lastname: Perkins
authors.affiliation: Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
authors.affiliation: Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Hemann
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|INSERM UMR 944, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Puissant
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Stegmaier
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D003198:Computer Simulation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D003402:Creatine Kinase / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D053858:Metabolic Networks and Pathways; D055432:Metabolomics; D008875:Middle Aged; D008928:Mitochondria; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000235:genetics*; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; C493728:RUNX1 protein, human; D014157:Transcription Factors; C519581:CKMT1A protein, human; D003402:Creatine Kinase