title: Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia.
abstract: Relapse of chronic myeloid leukemia (CML) is triggered by stem cells with a reconstituting capacity similar to that of hematopoietic stem cells (HSCs) and CML stem cells are a source of resistance in drug therapy with tyrosine kinase inhibitors (TKIs). Ecotropic viral integration site 1 (EVI1), a key transcription factor in HSC regulation, is known to predict poor outcomes in myeloid malignancies, however, incapability of prospective isolation of EVI1-high leukemic cells precludes the functional evaluation of intraindividual EVI1-high cells. Introduction of CML into Evi1-internal ribosomal entry site (IRES)-green fluorescent protein (GFP) knock-in mice, a versatile HSC-reporter strain, enables us to separate Evi1-high CML cells from the individual. Evi1-IRES-GFP allele models of CML in chronic phase (CML-CP), by retroviral overexpression of BCR-ABL and by crossing BCR-ABL transgenic mice, revealed that Evi1 is predominantly enriched in the stem cell fraction and associated with an enhanced proliferative as well as a leukemia-initiating capacity and that Evi1-high CML-CP cells exhibit resistance to TKIs. Overexpressing BCR-ABL and NUP98-HOXA9 in Evi1-IRES-GFP knock-in mice to model CML in blast crisis (CML-BC), in which Evi1-high cells turned to be a major population as opposed to a minor population in CML-CP models, showed that Evi1-high CML-BC cells have a greater potential to recapitulate the disease and appear resistant to TKIs. Furthermore, given that Evi1 heterozygosity ameliorates CML-CP and CML-BC development and that the combination of Evi1 and BCR-ABL causes acute myeloid leukemia resembling CML-BC, Evi1 could regulate CML development as a potent driver. In addition, in human CML-CP cases, we show that EVI1 is highly expressed in stem cell-enriched CD34+CD38-CD90+ fraction at single-cell level. This is the first report to clarify directly that Evi1-high leukemic cells themselves possess the superior potential to Evi1-low cells in oncogenic self-renewal, which highlights the role of Evi1 as a valuable and a functional marker of CML stem cells.
authors.affiliation: 1] Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan [2] Department of Transfusion Medicine, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Goyama
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Nasu
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tsuruta-Kishino
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kagoya
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nukina
authors.affiliation: Department of Metabolic and Diabetic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kumagai
authors.affiliation: Department of Metabolic and Diabetic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kubota
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Arai
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yoshimi
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Honda
authors.affiliation: Department of Metabolic and Diabetic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kadowaki
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001752:Blast Crisis / Q000378:metabolism*; D063646:Carcinogenesis / Q000378:metabolism; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology; D000074008:MDS1 and EVI1 Complex Locus Protein; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000502:physiology; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011519:Proto-Oncogenes; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; C400441:NUP98-HOXA9 fusion protein, human; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D016044:Fusion Proteins, bcr-abl
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