Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia

• Published in: Oncogene Vol. 33; no. 42; pp. 5028 - 5038
• Main Authors: Sato, T, Goyama, S, Kataoka, K, Nasu, R, Tsuruta-Kishino, T, Kagoya, Y, Nukina, A, Kumagai, K, Kubota, N, Nakagawa, M, Arai, S, Yoshimi, A, Honda, H, Kadowaki, T, Kurokawa, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.10.2014; Nature Publishing Group
• Subjects: 631/67/1059/2326; 631/67/1990/283/1896; 631/67/71; 692/420/755; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Biomarkers, Tumor - metabolism; Blast Crisis - metabolism; Carcinogenesis - metabolism; Cell Biology; Cell Proliferation; DNA-Binding Proteins - metabolism; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl - physiology; Gene Expression Regulation, Leukemic; Homeodomain Proteins - physiology; Human Genetics; Humans; Inhibitor drugs; Internal Medicine; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; MDS1 and EVI1 Complex Locus Protein; Medicine; Medicine & Public Health; Mice, Inbred C57BL; Mice, Knockout; Neoplastic Stem Cells - metabolism; Nuclear Pore Complex Proteins - physiology; Oncogene Proteins, Fusion - physiology; Oncology; Original; original-article; Phenotype; Protein expression; Protein Kinase Inhibitors - pharmacology; Proto-Oncogenes; Stem cells; Transcription Factors - metabolism; Up-Regulation
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.108

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.