title: Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2.
abstract: We previously reported that deficiency for Samd9L, which was cloned as a candidate gene for -7/7q- syndrome, accelerated leukemia cooperatively with enhanced expression of a histone demethylase: F-box and leucine-rich repeat protein 10 (Fbxl10, also known as Jhdm1b, Kdm2b, and Ndy1). To further investigate the role of Fbxl10 in leukemogenesis, we generated transgenic (Tg) mice that overexpress Fbxl10 in hematopoietic stem cells (HSCs). Interestingly, Fbxl10 Tg mice developed myeloid or B-lymphoid leukemia with complete penetrance. HSCs from the Tg mice exhibited an accelerated G0/G1-to-S transition with a normal G0 to G1 entry, resulting in pleiotropic progenitor cell expansion. Fbxl10 Tg HSCs displayed enhanced expression of neuron-specific gene family member 2 (Nsg2), and forced expression of Nsg2 in primary bone marrow cells resulted in expansion of immature cells. In addition, the genes involved in mitochondrial oxidative phosphorylation were markedly enriched in Fbxl10 Tg HSCs, coupled with increased cellular adenosine 5'-triphosphate levels. Moreover, chromatin immunoprecipitation followed by sequencing analysis demonstrated that Fbxl10 directly binds to the regulatory regions of Nsg2 and oxidative phosphorylation genes. These findings define Fbxl10 as a bona fide oncogene, whose deregulated expression contributes to the development of leukemia involving metabolic proliferative advantage and Nsg2-mediated impaired differentiation.
authors: Department of Disease Model and.
authors: Takeshi
authors: T
authors: Ueda
authors: Department of Molecular Oncology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan;
authors: Akiko
authors: A
authors: Nagamachi
authors: Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo, Japan;
authors: Keiyo
authors: K
authors: Takubo
authors: Department of Disease Model and.
authors: Norimasa
authors: N
authors: Yamasaki
authors: Department of Molecular Oncology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan;
authors: Hirotaka
authors: H
authors: Matsui
authors: Department of Molecular Oncology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan;
authors: Akinori
authors: A
authors: Kanai
authors: Department of Disease Model and.
authors: Yuichiro
authors: Y
authors: Nakata
authors: Department of Disease Model and.
authors: Kenichiro
authors: K
authors: Ikeda
authors: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
authors: Takaaki
authors: T
authors: Konuma
authors: Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan;
authors: Hideaki
authors: H
authors: Oda
authors: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD;
authors: Linda
authors: L
authors: Wolff
authors: Health Care Center and Graduate School of Humanities and Sciences, Institute of Environmental Science for Human Life, Ochanomizu University, Tokyo, Japan; and.
authors: Zen-ichiro
authors: Z
authors: Honda
authors: Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors: Xudong
authors: X
authors: Wu
authors: Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors: Kristian
authors: K
authors: Helin
authors: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
authors: Atsushi
authors: A
authors: Iwama
authors: Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo, Japan;
authors: Toshio
authors: T
authors: Suda
authors: Department of Molecular Oncology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan;
authors: Toshiya
authors: T
authors: Inaba
authors: Department of Disease Model and.
authors: Hiroaki
authors: H
authors: Honda
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes; D015854:Up-Regulation / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D044783:F-Box Proteins; D009419:Nerve Tissue Proteins; C000600524:Nsg2 protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases; C524747:Kdm2b protein, mouse