title: Association of a murine leukaemia stem cell gene signature based on nucleostemin promoter activity with prognosis of acute myeloid leukaemia in patients.
abstract: Acute myeloid leukaemia (AML) is a heterogeneous neoplastic disorder in which a subset of cells function as leukaemia-initiating cells (LICs). In this study, we prospectively evaluated the leukaemia-initiating capacity of AML cells fractionated according to the expression of a nucleolar GTP binding protein, nucleostemin (NS). To monitor NS expression in living AML cells, we generated a mouse AML model in which green fluorescent protein (GFP) is expressed under the control of a region of the NS promoter (NS-GFP). In AML cells, NS-GFP levels were correlated with endogenous NS mRNA. AML cells with the highest expression of NS-GFP were very immature blast-like cells, efficiently formed leukaemia colonies in vitro, and exhibited the highest leukaemia-initiating capacity in vivo. Gene expression profiling analysis revealed that cell cycle regulators and nucleotide metabolism-related genes were highly enriched in a gene set associated with leukaemia-initiating capacity that we termed the 'leukaemia stem cell gene signature'. This gene signature stratified human AML patients into distinct clusters that reflected prognosis, demonstrating that the mouse leukaemia stem cell gene signature is significantly associated with the malignant properties of human AML. Further analyses of gene regulation in leukaemia stem cells could provide novel insights into diagnostic and therapeutic approaches to AML.
authors: Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
authors: Mohamed A E
authors: MA
authors: Ali
authors: Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
authors: Kazuhito
authors: K
authors: Naka
authors: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
authors: Akiyo
authors: A
authors: Yoshida
authors: Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
authors: Kyoko
authors: K
authors: Fuse
authors: Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
authors: Atsuo
authors: A
authors: Kasada
authors: Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
authors: Takayuki
authors: T
authors: Hoshii
authors: Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
authors: Yuko
authors: Y
authors: Tadokoro
authors: Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
authors: Masaya
authors: M
authors: Ueno
authors: Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
authors: Kumiko
authors: K
authors: Ohta
authors: Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
authors: Masahiko
authors: M
authors: Kobayashi
authors: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
authors: Chiaki
authors: C
authors: Takahashi
authors: Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan. Electronic address: ahirao@staff.kanazawa-u.ac.jp.
authors: Atsushi
authors: A
authors: Hirao
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D019204:GTP-Binding Proteins / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*
chemical_list: C469949:GNL3 protein, human; D005819:Genetic Markers; D009687:Nuclear Proteins; D019204:GTP-Binding Proteins
keywords: Acute myeloid leukaemia; Leukaemia stem cells; Nucleostemin