Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia
| Autor: | Yuki Kagoya, Katsuyoshi Kumagai, Takashi Kadowaki, Masahiro Nakagawa, Hiroaki Honda, Naoto Kubota, Mineo Kurokawa, Ryo Nasu, Akihide Yoshimi, Arika Nukina, Susumu Goyama, Tomohiko Sato, Syunya Arai, Takako Tsuruta-Kishino, Keisuke Kataoka |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Myeloid Oncogene Proteins Fusion medicine.drug_class Carcinogenesis Population CD34 Fusion Proteins bcr-abl Antineoplastic Agents Biology Tyrosine-kinase inhibitor hemic and lymphatic diseases Leukemia Myelogenous Chronic BCR-ABL Positive Proto-Oncogenes Genetics medicine Biomarkers Tumor Animals Humans education Molecular Biology neoplasms Protein Kinase Inhibitors Cell Proliferation Homeodomain Proteins Mice Knockout education.field_of_study Gene Expression Regulation Leukemic Myeloid leukemia medicine.disease MDS1 and EVI1 Complex Locus Protein Up-Regulation DNA-Binding Proteins Mice Inbred C57BL Nuclear Pore Complex Proteins Leukemia Haematopoiesis Leukemia Myeloid Acute medicine.anatomical_structure Phenotype Drug Resistance Neoplasm Immunology Cancer research Neoplastic Stem Cells Original Article Stem cell Blast Crisis Transcription Factors |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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